US7973057B2 - Thalidomide analogs - Google Patents

Thalidomide analogs Download PDF

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US7973057B2
US7973057B2 US10/572,485 US57248506A US7973057B2 US 7973057 B2 US7973057 B2 US 7973057B2 US 57248506 A US57248506 A US 57248506A US 7973057 B2 US7973057 B2 US 7973057B2
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sulfur
compound
substituted
tnf
thalidomide
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US20060211728A1 (en
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Nigel H. Greig
Harold Holloway
Arnold Brossi
Xiaoxiang Zhu
Tony Giordano
Qian-Sheng Yu
William D. Figg
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GOVERNMENT OF UNITED STATES HEALTH AND HUMAN SERVICES THE, Secretary of, Department of
P2D Inc
US Department of Health and Human Services
Phase 2 Discovery Inc
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US Department of Health and Human Services
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Assigned to GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, THE reassignment GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FIGG, WILLIAM D., GREIG, NIGEL H., HOLLOWAY, HAROLD, ZHU, XIAOXIANG, YU, QIAN-SHENG
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Assigned to P2D INC. reassignment P2D INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BROSSI, ARNOLD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to thalidomide analogs, methods of synthesizing the analogs, and methods for using the analogs to modulate angiogenesis and tumor necrosis factor alpha activities in a subject. More particularly, the invention relates to sulfur-containing thalidomide analogs and methods of making and using the same.
  • Thalidomide N- ⁇ -phthalimidoglutarimide
  • Thalidomide is a glutamic acid derivative that was introduced onto the market as a sedative hypnotic in 1956, but was withdrawn in 1961 due to the development of severe congenital abnormalities in babies born to mothers using it for morning sickness.
  • Interest in the agent was reawakened after thalidomide was found clinically effective in the treatment of erythema nodosum leprosum (ENL) and in the treatment of HIV wasting syndrome and various cancers.
  • ENL erythema nodosum leprosum
  • Mechanistic studies of its ENL activity demonstrated an anti-tumor necrosis factor alpha (anti-TNF- ⁇ ) action.
  • thalidomide enhances the degradation of TNF- ⁇ RNA, and thereby lowers its synthesis and secretion.
  • TNF- ⁇ and family members play pivotal roles in a variety of physiological and pathological processes, which include cell proliferation and differentiation, apoptosis, the modulation of immune responses and induction of inflammation
  • TNF- ⁇ acts via two receptors, TNFR1 and 2.
  • the former is expressed in all tissues and is the predominant signaling receptor for TNF- ⁇ .
  • the latter is primarily expressed on immune cells and mediates more limited biological responses.
  • the exposure of cells to TNF- ⁇ can result in activation of a caspase cascade leading to cell death via apoptosis.
  • major cell surface molecules capable of initiating apoptosis are members of the TNF family of ligands and receptors.
  • death-inducing members of the TNF receptor family each contain a cytoplasmic ‘death domain’ (DD), which is a protein-protein interaction motif critical for engaging downstream components of the signal transduction machinery.
  • DD cytoplasmic ‘death domain’
  • TRAIL the tumor necrosis factor-related apoptosis-inducing ligand
  • TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases. More often, however, TNF- ⁇ receptor binding induces the activation of transcription factors, AP-1 and NF ⁇ B, that thereafter induce genes involved in acute and chronic inflammatory responses.
  • TNF- ⁇ has thus been implicated in many inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease and Crohn's disease, and it additionally exacerbates ENL, septic shock, AIDS and dementia associated with Alzheimer's disease (AD).
  • rheumatoid arthritis graft-versus-host disease and Crohn's disease
  • AD Alzheimer's disease
  • thalidomide analogs optimized to reduce TNF- ⁇ synthesis have been designed and synthesized. Primarily, these analogs include structural modifications of the phthaloyl ring or glutarimide ring of thalidomide.
  • syntheses of the hydroxylated and hydrolysis metabolites as inhibitors of angiogenesis or tumor metastasis have been reported.
  • extensive studies exist regarding the structure-activity relationships between thalidomide and TNF- ⁇ very little is known about the contribution of the four amide carbonyl groups of thalidomide to its biological activity.
  • Thalidomide analogs having angiogenesis modulating activity and TNF- ⁇ modulating activity are disclosed.
  • the disclosed thalidomide analogs are sulfur-analogs of thalidomide, its open-ring metabolites and its derivatives (such as its hydroxylated derivatives) in which one or more carbonyl groups are replaced by thiocarbonyl groups.
  • thalidomide analogs wherein at least one carbonyl group on the pthaloyl moiety or on the glutaramide moiety (or its open ring form) of a thalidomide or a thalidomide analog is replaced by a thiocarbonyl group.
  • successive replacement of the carbonyl groups in thalidomide with thiocarbonyl groups provides thiothalidomide analogs having increased TNF- ⁇ inhibitory activity.
  • the increase in TNF- ⁇ inhibition due to replacement of the carbonyl groups of thalidomide with thiocarbonyl groups is not associated with toxicity.
  • Improved methods for making thalidomide and thalidomide analogs are also disclosed, as are methods of converting thalidomide analogs into thiothalidomides. Due to their angiogenesis and TNF- ⁇ modulating activity, the disclosed thalidomide analogs, especially the disclosed thiothalidomides, can be used to treat a subject having a disease or condition related to angiogenesis or TNF- ⁇ activity, such as a tumor or unwanted neovascularization. Furthermore, the physical and toxicological properties of the disclosed thiothalidomide analogs make them suitable for potently and safely modulating angiogenesis and TNF- ⁇ activity without injection, for example, by oral administration. This is in contrast to many currently available agents used for such purposes.
  • FIG. 1 is a bar graph showing the TNF- ⁇ inhibitory action of several disclosed thalidomide analogs in murine cells having a luciferase reporter element plus the 3′-UTR of human TNF- ⁇ relative to their action in cells lacking the 3′UTR.
  • FIG. 2 is a bar graph showing the relative angiogenic modulating activity of 1,3-Dioxo-2-(2-hydroxy-6-methoxypyridin-3-yl)-isoindoline hydrobromide at several concentrations.
  • FIG. 3 is a bar graph showing the relative angiogenic modulating activity of 2-(3-cyclohexenyl)-H-isoindol-1,3(2H)-dithione at several concentrations.
  • FIG. 4 is a bar graph showing the relative angiogenic modulating activity of 1-(2,6-Dithioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione at several concentrations.
  • FIG. 5 is a bar graph showing the relative angiogenic modulating activity of 3-Camphanic amino-2,6-piperidinedione at several concentrations.
  • FIG. 6 is a bar graph showing the relative angiogenic modulating activity of Dithiophthalimide at several concentrations.
  • FIG. 7 is a bar graph showing the relative angiogenic modulating activity of 2-(1,3-Dihydro-1-oxo-3-thioxo-2H-isoindol-2-yl)-pentanedioic acid at several concentrations.
  • FIG. 8 is a bar graph showing the relative angiogenic modulating activity of 2-(2-Oxo-6-thioxo-3-piperidinyl)-1H-isoindole-1,3(2H) -dione at several concentrations.
  • FIG. 9 is a bar graph showing the relative angiogenic modulating activity of 2,3-Dihydro-3-thioxo-2-(2,6-dithioxo-3-piperidinyl)-1H -isoindol-1-one at several concentrations.
  • FIG. 10 is a bar graph showing the relative angiogenic modulating activity of 2-Acetoxy-N-(2,6-dioxopiperidin-3-yl)benzamide at several concentrations.
  • FIG. 11 is a bar graph showing the relative angiogenic modulating activity of 1,3-Dioxo-2-(2,6-dimethoxypyridin-3-yl)-isoindoline at several concentrations.
  • TNF- ⁇ tumor necrosis factor alpha
  • ARE adenylate/uridylate (AU)-rich element
  • subject refers to animals, including mammals (for example, humans and veterinary animals such as dogs, cats, pigs, horses, sheep, and cattle).
  • R-group refers to a single atom (for example, a halogen atom) or a group of two or more atoms that are covalently bonded to each other, which are covalently bonded to an atom or atoms in a molecule to satisfy the valency requirements of the atom or atoms of the molecule, typically in place of a hydrogen atom.
  • R-groups/substituents include alkyl groups, hydroxyl groups, alkoxy groups, acyloxy groups, mercapto groups, and aryl groups.
  • “Substituted” or “substitution” refer to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups such as halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl, piperazin-1-yl, nitro, sulfato or other R-groups.
  • additional R-groups such as halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryl, arylalkyl, heteroaryl, amino, alkylamino, dialkylamino, morpholino, piperidino, pyr
  • Alkyl refers to a cyclic, branched, or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms. This term is further exemplified by groups such as methyl, ethyl, n-propyl, isobutyl, t-butyl, pentyl, pivalyl, heptyl, adamantyl, and cyclopentyl. Alkyl groups can either be unsubstituted or substituted. “Lower alkyl” groups are those that contain one to six carbon atoms.
  • “Acyl” refers to a group having the structure RCO—, where R may be alkyl, or substituted alkyl. “Lower acyl” groups are those that contain one to six carbon atoms.
  • acyloxy refers to a group having the structure RCOO—, where R may be alkyl or substituted alkyl.
  • Lower acyloxy groups contain one to six carbon atoms.
  • Alkenyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to six carbon atoms.
  • Alkynyl refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. “Lower alkynyl” groups are those that contain one to six carbon atoms.
  • Alkoxy refers to a group having the structure R—O—, where R may be alkyl or substituted alkyl. Examples of alkoxy groups include methoxy, ethoxy, propoxy and butoxy groups. “Lower alkoxy” groups are those that contain one to six carbon atoms.
  • halogen refers to fluoro, bromo, chloro and iodo substituents.
  • Aryl refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted.
  • amino refers to an R-group having the structure —NH 2 , which can be optionally substituted with, for example, lower alkyl groups, to yield an amino group having the general structure —NHR or —NR 2 .
  • Niro refers to an R-group having the structure —NO 2 .
  • aliphatic as applied to cyclic groups refers to ring structures in which any double bonds that are present in the ring are not conjugated around the entire ring structure.
  • aromatic refers to ring structures which contain double bonds that are conjugated around the entire ring structure, possibly through a heteroatom such as an oxygen atom or a nitrogen atom.
  • Aryl groups, pyridyl groups and furan groups are examples of aromatic groups.
  • the conjugated system of an aromatic group contains a characteristic number of electrons, for example, 6 or 10 electrons that occupy the electronic orbitals making up the conjugated system, which are typically un-hybridized p-orbitals.
  • “Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically-acceptable excipients, including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients.
  • Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa. (19th Edition).
  • a “therapeutically effective amount” of the disclosed compounds is a dosage of the compound that is sufficient to achieve a desired therapeutic effect, such as inhibition of angiogenesis or an anti-tumor or anti-metastatic effect, or inhibition of TNF- ⁇ activity.
  • a therapeutically effective amount is an amount sufficient to achieve tissue concentrations at the site of action that are similar to those that are shown to modulate angiogenesis or TNF- ⁇ activity in tissue culture, in vitro, or in vivo.
  • a therapeutically effective amount of a compound may be such that the subject receives a dosage of about 0.1 ⁇ g/kg body weight/day to about 1000 mg/kg body weight/day, for example, a dosage of about 1 ⁇ g/kg body weight/day to about 1000 ⁇ g/kg body weight/day, such as a dosage of about 5 ⁇ g/kg body weight/day to about 500 ⁇ g/kg body weight/day.
  • stereoisomer refers to a molecule that is an enatiomer, diasteromer or geometric isomer of a molecule. Stereoisomers, unlike structural isomers, do not differ with respect to the number and types of atoms in the molecule's structure but with respect to the spatial arrangement of the molecule's atoms. Examples of stereoisomers include the (+) and ( ⁇ ) forms of optically active molecules.
  • modulate refers to the ability of a disclosed compound to alter the amount, degree, or rate of a biological function, the progression of a disease, or amelioration of a condition.
  • modulating can refer to the ability of a compound to elicit an increase or decrease in angiogenesis, to inhibit TNF- ⁇ activity, or to inhibit tumor metastasis or tumorigenesis.
  • angiogenic activity refers to the ability of a disclosed compound or a particular concentration of a disclosed compound to stimulate angiogenesis. Angiogenic activity may be detected in vivo or in vitro. Angiogenic compounds or angiogenic concentrations of disclosed compounds stimulate angiogenesis, and such compounds and/or concentrations may be readily identified by those of ordinary skill in the art, using, for example, the methods described in the Examples that follow.
  • anti-angiogenic activity refers to the ability of a compound or a particular concentration of a disclosed compound to inhibit angiogenesis. Anti-angiogenic activity may be detected in vivo or in vitro. Anti-angiogenic or anti-angiogenic concentrations of disclosed compounds inhibit angiogenesis, and such compounds and/or concentrations may be readily identified by those of ordinary skill in the art, using, for example, the methods described in the Examples that follow.
  • thalidomide analogs that modulate TNF- ⁇ activity and/or angiogenesis, and as such can be used to treat a wide variety of pathological conditions that are linked to angiogenesis and/or TNF- ⁇ activity.
  • Pharmaceutically acceptable salts, stereoisomers, and metabolites of all of the disclosed compounds also are contemplated.
  • the thalidomide analogs are thiothalidomide derivatives in which carbonyl groups in corresponding non-sulfur-containing thalidomide derivatives are replaced by one or more thiocarbonyl groups.
  • the disclosed compounds include compounds having the chemical formula:
  • X and Y are independently CH 2 , oxygen or sulfur, and at least one of X and Y is sulfur if R 1 does not include a sulfur atom; each of R 2 -R 5 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen, nitro or linked to form a five- or six-membered, unsubstituted or substituted, aliphatic, aromatic or heterocyclic ring, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R 1 is an unsubstituted or substituted, aliphatic or aromatic heterocyclic ring, an unsub
  • W and Z are each independently oxygen or sulfur
  • R 6 and R 7 are each independently hydroxyl, alkoxy or substituted alkoxy
  • each of R 8 -R 12 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted ally, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl.
  • R 1 is
  • W and Z are each independently oxygen or sulfur
  • R 13 and R 14 are each independently hydrogen, alkyl or substituted alkyl
  • R 20 is hydrogen, hydroxyl, alkyl or substituted alkyl such as aryl substituted alkyl
  • R 15 -R 19 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl.
  • At least one of R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 15 , R 16 , R 17 , R 18 and R 19 is hydroxyl.
  • at least one of X, Y, W and Z is sulfur, at least two of X, Y, W and Z are sulfur, or at least three of X, Y, W and Z are sulfur.
  • X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present.
  • W and Z are present the following are possible: X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ S, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ S,
  • the disclosed compounds have the formula
  • X, Y, W and Z are independently sulfur or oxygen and at least one of X, Y, W and Z is sulfur, and R 2 -R 12 are as before.
  • X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present.
  • W and Z are present the following are possible: X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ S, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ S, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ S,
  • the disclosed compounds have the chemical formula:
  • W, X, Y and Z each are independently sulfur or oxygen and at least one of W, X, Y and Z is sulfur; and R 2 -R 5 and R 15 -R 20 are as before.
  • X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur.
  • the disclosed compounds also include compounds having the formula
  • R 21 -R 25 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R 26 is
  • W, Z and R 13 -R 20 are as before.
  • T or V is sulfur, and both W and Z are oxygen if present; both T and V are sulfur and both W and Z are oxygen if present; T and V are both oxygen and W or Z is sulfur if present; both T and V are sulfur and W or Z is sulfur if present; or T or V are sulfur and both W and Z are sulfur if present.
  • the disclosed compounds include compounds having the formula
  • R 27 -R 33 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R 34 is hydrogen, alkyl or substituted alkyl.
  • X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur.
  • the disclosed compounds include compounds having the formula
  • X and Y are each independently oxygen or sulfur; W, Z, R 15 -R 20 and R 34 are as before, R 35 is alkyl or substituted alkyl, and R 36 -R 39 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl.
  • X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur.
  • X and Y each are independently oxygen or sulfur; W, Z and R 15 -R 20 are as before; and R 40 -R 45 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl.
  • X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfur and both W and Z are sulfur.
  • the disclosed compounds further include compounds having the formula
  • X Y, W and Z are independently oxygen or sulfur, and R 2 -R 5 and R 13 -R 16 are as before.
  • X or Y is sulfur, and both W and Z are oxygen; both X and Y are sulfur and both W and Z are oxygen; X and Y are both oxygen and W or Z is sulfur; both X and Y are sulfur and W or Z is sulfur; or X or Y are sulfa and both W and Z are sulfur.
  • thalidomide analog compound having the formula
  • X, Y and Z are independently oxygen or sulfur, and R 2 -R 5 , R 15 -R 20 and R 34 are as before.
  • X or Y is sulfur, and Z is oxygen; both X and Y are sulfur and Z is oxygen; X and Y are both oxygen and Z is sulfur.
  • thalidomide analog compound having the formula
  • R 1 is
  • W, Z, and R 13 -R 20 are as before.
  • X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present.
  • W and Z are present the following are possible: X ⁇ O, Y ⁇ O, W ⁇ O, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ S, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S,
  • X, Y are independently oxygen or sulfur
  • W, Z, R 2 , R 4 , R 5 , and R 13 -R 16 are as before.
  • X or Y is sulfur, and both W and Z are oxygen
  • both X and Y are sulfur and both W and Z are oxygen
  • X and Y are both oxygen and W or Z is sulfur
  • both X and Y are sulfur and W or Z is sulfur
  • or X or Y are sulfur and both W and Z are sulfur.
  • G and D are each independently oxygen or sulfur, R 2 -R 5 are as before, and R 46 is
  • W, Z and R 13 -R 20 are as before.
  • G or D is sulfur, and both W and Z are oxygen; both G and D are sulfur and both W and Z are oxygen; G and D are both oxygen and W or Z is sulfur; both G and D are sulfur and W or Z is sulfur; or G or D are sulfur and both W and Z are sulfur.
  • a method for modulating TNF- ⁇ activity in a subject also is disclosed.
  • the method includes administering to the subject a therapeutically effective amount of one or more of any of the compounds disclosed above, or a compound having the formula:
  • R 47 -R 52 are each independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl;
  • n 1-5;
  • X is oxygen or sulfur, and R 2 -R 5 and R 15 -R 19 are as before;
  • R 53 and R 54 are independently hydrogen, hydroxyl, acyl, substituted acyl, acyloxy, substituted acyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, amino, substituted amino, halogen or nitro, for example, hydrogen, lower alkyl, acyloxy, halogen, hydroxyl, amino or nitro such as hydrogen, acyloxy or hydroxyl; and R 55 is hydrogen, alkyl, or substituted alkyl; or a compound having the formula:
  • R 2 -R 5 are as before and R 56 is hydrogen, alkyl or substituted alkyl;
  • Novel thio-substituted analogs having the structures described with respect to the method above also are contemplated.
  • X or Y is sulfur, and both W and Z are oxygen if present; both X and Y are sulfur and both W and Z are oxygen if present; X and Y are both oxygen and W or Z is sulfur if present; both X and Y are sulfur and W or Z is sulfur if present; or X or Y are sulfur and both W and Z are sulfur if present.
  • W and Z are present, the following are possible: X ⁇ O, Y ⁇ O, W ⁇ O, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ O, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ S, Y ⁇ S, W ⁇ O, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ S, Z ⁇ O; X ⁇ S, Y ⁇ O, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ O, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ O, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S, W ⁇ S, Z ⁇ S; X ⁇ O, Y ⁇ S
  • Particularly disclosed compounds and compounds that can be used in the disclosed methods include one or more compounds having the following structures:
  • a method for modulating angiogenesis in a subject includes administering to the subject a therapeutically effective amount of one or more of any of the disclosed compounds. Examples of compounds useful for the method are shown above.
  • the therapeutically effective amount of the compound can be administered to a subject with a tumor to achieve an anti-tumor effect, such as inhibition of tumorigenesis or tumor metastasis.
  • the therapeutically effective amount of the compound is administered to a subject with a pathological angiogenesis.
  • stimulation of angiogenesis is desired an angiogenic compound or an angiogenic concentration of a compound is administered to a subject to stimulate angiogenesis.
  • the disclosed compounds are useful in the treatment of both primary and metastatic solid tumors, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract, (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes, and meninges (including
  • Such compounds may also be useful in treating solid tumors arising from hematopoietic malignancies such as leukemias (i.e. chloromas, plasmacytomas and the plaques and tumors of mycosis fungoides and cutaneous T-cell lymphoma/leukemia) as well as in the treatment of lymphomas (both Hodgkin's and non-Hodgkin's lymphomas).
  • leukemias i.e. chloromas, plasmacytomas and the plaques and tumors of mycosis fungoides and cutaneous T-cell lymphoma/leukemia
  • lymphomas both Hodgkin's and non-Hodgkin's lymphomas.
  • these compounds may be useful in the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic agents.
  • anti-angiogenic compounds/concentrations include the treatment and prophylaxis of autoimmune diseases such as rheumatoid, immune and degenerative arthritis.
  • Such compounds can also be used to treat a pathological (i.e. abnormal, harmful or undesired) angiogenesis, for example, various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other abnormal neovascularization conditions of the eye; skin diseases such as psoriasis; blood vessel diseases such as hemagiomas, and capillary proliferation within atherosclerotic plaques; Osler-Webber Syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; hemophiliac joints;
  • Other uses include the treatment of diseases characterized by excessive or abnormal stimulation of endothelial cells, including but not limited to intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and hypertrophic scars, such as keloids.
  • Another use is as a birth control agent, by inhibiting ovulation and establishment of the placenta.
  • the disclosed compounds are also useful in the treatment of diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele minalia quintosa) and ulcers ( Helicobacter pylori ).
  • the disclosed compounds are also useful to reduce bleeding by administration prior to surgery, especially for the treatment of resectable tumors.
  • Angiogenic compounds or angiogenic concentrations of disclosed compound can be used can be used to treat a variety of conditions that would benefit from stimulation of angiogenesis, stimulation of vasculogenesis, increased blood flow, and/or increased vascularity.
  • conditions and diseases amenable to treatment using disclosed angiogenic compounds, or angiogenic concentrations of disclosed compounds include any condition associated with an obstruction of a blood vessel, such as obstruction of an artery, vein, or of a capillary system.
  • conditions or disease include, but are not necessarily limited to, coronary occlusive disease, carotid occlusive disease, arterial occlusive disease, peripheral arterial disease, atherosclerosis, myointimal hyperplasia (such as due to vascular surgery or balloon angioplasty or vascular stenting), thromboangiitis obliterans, thrombotic disorders, vasculitis, and the like.
  • coronary occlusive disease carotid occlusive disease
  • arterial occlusive disease e.g., arterial occlusive disease
  • peripheral arterial disease e.g., atherosclerosis
  • myointimal hyperplasia such as due to vascular surgery or balloon angioplasty or vascular stenting
  • thromboangiitis obliterans thrombotic disorders
  • vasculitis e.g., vasculitis
  • angiogenesis stimulation includes, but are not necessarily limited to accelerating healing of wounds or ulcers; improving the vascularization of skin grafts or reattached limbs so as to preserve their function and viability; improving the healing of surgical anastomoses (such as in reconnecting portions of the bowel after gastrointestinal surgery); and improving the growth of skin or hair.
  • a method for inhibiting TNF- ⁇ activity in a subject using the disclosed compounds includes administering a therapeutically effective amount of a disclosed compound to a subject to achieve a TNF- ⁇ inhibitory effect.
  • the disclosed compounds having TNF- ⁇ inhibitory effects are useful for treating many inflammatory, infectious, immunological, and malignant diseases.
  • septic shock include but are not limited to septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis and other dermal diseases, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, tumor growth, undesirable angiogenesis, autoimmune disease, opportunistic infections in ADS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, radiation damage, and hyperoxic alveolar injury.
  • the compounds can be used to treat other neurodegenerative diseases as exemplified by Alzheimer's disease, Parkinson's disease, head trauma, stroke and ALS.
  • the disclosed compounds can be used in combination with other compositions and procedures for the treatment of diseases.
  • a tumor can be treated conventionally with surgery, radiation or chemotherapy in combination with an anti-angiogenic compound/concentration and then, optionally the compound/concentration can be further administered to the subject to extend the dormancy of micrometastases and to stabilize and inhibit the growth of any residual primary tumor.
  • an angiogenic compound or angiogenic concentration of a compound can be used in combination with other angiogenesis stimulating agents.
  • thermal energy in the form of resistive heating, laser energy or both
  • thermally treated stimulation zones or pockets (optionally interconnected, at least initially, by small channels) in the tissue for the introduction of blood born growth and healing factors, along with stimulated capillary growth surrounding the thermally treated zone.
  • Such simulation zones allow increased blood flow to previously ischemic and/or nonfunctional tissue (such as cardiac tissue) with a concomitant increased supply of oxygen and nutrients ultimately resulting in a revitalization of the treated sections the tissue when used in combination with the angiogenic compositions/concentrations.
  • disclosed compounds exhibiting TNF- ⁇ inhibitory activity can be combined with other TNF- ⁇ inhibitory agents, for example, steroids such as dexamethasone and prednisolone.
  • the compounds can be used in combination with chemotherapeutic agents and/or radiation and/or surgery.
  • Examples of other chemotherapeutic agents that can be used in combination with the disclosed compounds include alkylating agents, antimetabolites, natural products, kinase inhibitors, hormones and their antagonists, and miscellaneous other agents.
  • alkylating agents include nitrogen mustards (such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard or chlorambucil), alkyl sulfonates (such as busulfan), and nitrosoureas (such as carmustine, lomustine, semustine, streptozocin, or dacarbazine).
  • antimetabolites include folic acid analogs (such as methotrexate), pyrimidine analogs (such as 5-FU or cytarabine), and purine analogs, such as mercaptopurine or thioguanine.
  • natural products include vinca alkaloids (such as vinblastine, vincristine, or vindesine), epipodophyllotoxins (such as etoposide or teniposide), antibiotics (such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, or mitocycin C), and enzymes (such as L-asparaginase).
  • kinase inhibitors examples include small molecule inhibitors (such as Iressa, Tarceva, PKI-166, CI-1033, CGP-5923A, EKB-569, TAK165, GE-572016, CI-1033, SU5416, ZD4190, PTK787/ZK222584, CGP41251, CEP-5214, ZD6474, BIBF1000, VGA1102, SU6668, SU11248, CGP-57148, tricyclic quinoxalines, SU4984, SU5406, Gleevec, NSC680410, PD166326, PD1173952, CT53518, GTP14564, PKC412, PP1, PD116285, CGP77675, CGP76030, CEP-701, and CEP2583), ligand modulators (such as Bevacizumanb, MV833, Soluble Flt-1 and Flk-1, VEGF Trap, GFB 116, NM3, VEGF
  • hormones and antagonists include adrenocorticosteroids (such as prednisone), progestins (such as hydroxyprogesterone caproate, medroxyprogesterone acdtate, and magestrol acetate), estrogens (such as diethylstilbestrol and ethinyl estradiol), antiestrogens (such as tamoxifen), and androgens (such as testerone proprionate and fluoxymesterone).
  • adrenocorticosteroids such as prednisone
  • progestins such as hydroxyprogesterone caproate, medroxyprogesterone acdtate, and magestrol acetate
  • estrogens such as diethylstilbestrol and ethinyl estradiol
  • antiestrogens such as tamoxifen
  • androgens such as testerone proprionate and fluoxymesterone
  • miscellaneous agents include platinum coordination complexes (such as cis-diamine-dichloroplatinum II, which is also known as cisplatin), substituted ureas (such as hydroxyurea), methyl hydrazine derivatives (such as procarbazine), vaccines (such as APC8024), AP22408, B43-genistein conjugate, paclitaxel, AG538, and adrenocrotical suppressants (such as mitotane and aminoglutethimide).
  • platinum coordination complexes such as cis-diamine-dichloroplatinum II, which is also known as cisplatin
  • substituted ureas such as hydroxyurea
  • methyl hydrazine derivatives such as procarbazine
  • vaccines such as APC8024
  • AP22408 B43-genistein conjugate
  • paclitaxel paclitaxel
  • AG538 adrenocrotical suppressants
  • the disclosed compounds can be combined with gene therapy approaches, such as those targeting VEGF/VEGFR (including antisense oligonucleotide therapy, Adenovirus-based Flt-1 gene therapy, Retrovirus-base Flk-1 gene therapy, Retrovirus-based VHL gene therapy, and angiozyme) and IGF-1R (including INX-4437).
  • gene therapy approaches such as those targeting VEGF/VEGFR (including antisense oligonucleotide therapy, Adenovirus-based Flt-1 gene therapy, Retrovirus-base Flk-1 gene therapy, Retrovirus-based VHL gene therapy, and angiozyme) and IGF-1R (including INX-4437).
  • Examples of the most commonly used chemotherapy drugs that can be used in combination with the disclosed tricyclic compounds agent include Adriamycin, Alkeran, Ara-C, BiCNU, Busulfan, CCNU, Carboplatinum, Cisplatinum, Cytoxan, Daunorubicin, DTIC, 5-FU, Fludarabine, Hydrea, Idarubicin, Ifosfamide, Methotrexate, Mithramycin, Mitomycin, Mitoxantrone, Nitrogen Mustard, Taxol, Velban, Vincristine, VP-16, Gemcitabine (Gemzar), Herceptin, Irinotecan (Camptosar, CPT-11), Leustatin, Navelbine, Rituxan STI-571, Taxotere, Topotecan (Hycamtin), Xeloda (Capecitabine), Zevelin and calcitriol.
  • the disclosed compounds also can be combined with radiotherapy employing radioisotopes (such as 32 P, 90 Y, 125 I, 131 I, and 177 Lu), particle beams (such as proton, neutron and electron beams) and electromagnetic radiation (such as gamma rays, x-rays and photodynamic therapy using photosensitizers and visible or ultraviolet rays).
  • radioisotopes such as 32 P, 90 Y, 125 I, 131 I, and 177 Lu
  • particle beams such as proton, neutron and electron beams
  • electromagnetic radiation such as gamma rays, x-rays and photodynamic therapy using photosensitizers and visible or ultraviolet rays.
  • compositions including one or more of any of the compounds disclosed above and a pharmaceutically acceptable carrier.
  • the composition may comprise a unit dosage form of the composition, and may further comprise instructions for administering the composition to a subject to inhibit angiogenesis, for example, instructions for administering the composition to achieve an anti-tumor effect or to inhibit a pathological angiogenesis.
  • the pharmaceutical composition may comprise one or more of 1-Thioxo-3-oxo-2-(2-oxo-6-thioxopiperidin-3-yl)isoindoline, 1,3-Dioxo-2-(2,6-dithioxopiperidin-3-yl)isoindoline, 1-Thioxo-3-oxo-2-(2,6-dithioxopiperidin-3-yl)isoindoline, N-(2,6-dioxopiperidin-3-yl)-2,3-naphthalenedicarboxamide, 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-5-azaisoindoline, 1,3-Dioxo-2-(1-phenethyl-2,6-dioxopiperidin-3-yl)isoindoline, 2-Acetoxy-N-(2,6-dioxopiperidin-3-yl)benzyl-N
  • compositions are compounded for oral administration, and such oral dosage forms can include one or more of any of the disclosed compounds including those compounds particularly disclosed by their IUPAC names above.
  • Such pharmaceutical compositions may be used in methods for modulating angiogenesis or TNF- ⁇ activity in a subject by administering to the subject a therapeutically effective amount of the composition.
  • thionation of thalidomide analogs to replace carbonyl groups with thiocarbonyl groups can provide thalidomide analogs with increased TNF- ⁇ activity, increased angiogenic activity or increased anti-angiogenic activity.
  • the compounds are shown with carbonyl groups, it is to be understood that thionated derivatives of such compounds are also part of the disclosure.
  • 2,6-Dioxo-3-(t-butoxycarbonylamino)piperidine (3) was prepared and isolated as follows. A solution of N-(t-butoxycarbonyl)-L-glutamine (4.92 g) and carbonyl diimidazole (1.70 g) in THF (100 mL) was refluxed for 9 h.
  • dimethylether 5 was obtained by condensation of aminopyridine with phthalic anhydride in refluxing AcOH in the presence of sodium acetate. On standing with HBr in glacial AcOH solution (30%) at room temperature for 18 h, selective ether cleavage of 5 was accomplished to give compound 6.
  • the structure of compound 6 was determined by mass spectroscopy, 1D NMR and 2D NMR. The molecular ion for compound 6 is 270 amu, demonstrating that only one methyl ether was cleaved. 2D NOESY showed that protons on the methoxy group correlated with H-5, indicating that the 2-methoxy was selectively cleaved and that the 6-methoxy remained.
  • the reaction temperature elevated to 70° C. both methyl ethers were cleaved with HBr/HOAc solution (30%) to give diol 7.
  • 1,3-Dioxo-2-(2,6-dimethoxypyridin-3-yl)-isoindoline (5) was prepared and isolated as follows. A mixture of phthalic anhydride (0.89 g, 6 mmol), 3-amino -2,6-dimethoxypyridine monohydrochloride (95%, 1 g, 5 mmol) and sodium acetate (0.49 g, 6 mmol) in glacial acetic acid (50 ml) was refluxed for 3 h. The solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 ml) and washed with water (100 ml ⁇ 3), dried over Na 2 SO 4 and concentrated to give the crude product.
  • 1,3-Dioxo-2-(2-hydroxy-6-methoxypyridin-3-yl)-isoindoline hydrobromide (6) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (155 mg, 0.546 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at room temperature under N 2 for 18 h. Dry ether was added slowly until the solution became cloudy.
  • 1,3-Dioxo-2-(2,6-dihydroxypyridin-3-yl)-isoindoline hydrobromide (7) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (150 mg, 0.528 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at an 70° C. oil bath under N 2 for 54 h. The mixture was cooled to room temperature, dry ether was added, and the supernatant liquid was decanted.
  • 1,3-Dioxo-2-(1-phenethyl-2,6-dioxopiperidin-3-yl)isoindoline (8) was specifically prepared and isolated as follows. A mixture of N-phthaloyl-DL-glutamic anhydride (300 mg, 1.13 mmol) and phenethylamine (139 mg, 1.13 mmol) was stirred in a 177° C. oil bath for two hours.
  • azathalidomide was prepared from aminoglutarimide and commercial pyridine-3,4-dicarboxylic anhydride.
  • Cbz-aminoglutarimide was deprotected by hydrogenolysis with catalyst palladium hydroxide on carbon (10%) to form aminoglutarimide.
  • Pyridine-3,4-dicarboxyic anhydride was refluxed with aminoglutarimide in the presence of triethylamine to yield azathalidomide 11 in the total yield of 17% from Cbz-aminoglutarimide.
  • 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-5-azaisoindoline (11) was prepared specifically as follows. A mixture of Cbz-aminoglutarimide (302 mg) and palladium hydroxide on carbon (20%) in 2-propanol (20 ml) was stirred under H 2 for one day. The reaction mixture was filtered through celite and washed with 2-propanol and methanol. The combined filtrate was concentrated to afford crude 3-amino-1,6-dioxopiperidine as syrup.
  • acetoxythalidomide was prepared and isolated as follows. First, 3-Acetoxyphathalic anhydride was prepared by refluxing a mixture of 3-hydroxyphthalic anhydride (150 mg), acetic anhydride (2 mL), and NaOAc (150 mg) for 8 h. The reaction mixture was filtered. The filtrate was concentrated and washed with dry ether to give a pale yellow solid (127 mg, 68%).
  • 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline was prepared and isolated as follows. A mixture of 3-acetoxyphthalic anhydride (40 mg), aminoglutarimide trifluoroacetate (47 mg), and NaOAc (32 mg) in acetic acid (2 mL) was refluxed for 5 h. The solvent was evaporated, water (10 mL) was added, and the resulting solution was stirred for several minutes.
  • N-(2,6-dioxopiperidin-3-yl)-1,8-naphthalimide (12) was prepared and isolated as follows. A mixture of amine 4 (0.877 mmol), 1,8-naphthalic anhydride (174 mg, 0.879) and triethylamine (1.22 ml) in THF (10 ml) was refluxed for 20 h. The solvent was removed and the residue was suspended in acetic anhydride and refluxed for 20 minutes. Ethanol (5 ml) was added at 80° C. and stirred for 30 min.
  • N-2,6-dioxopiperidin-3-yl)-2,3-naphthalenedicarboxamide (14) was prepared and isolated as follows. A mixture of 2,3-naphthalenedicarboxylic acid (199 mg, 0.875 mmol) and acetic anhydride (2 mL) was refluxed for 30 min. The reaction mixture was cooled down, and the solid was collected by filter to afford anhydride 13 (0.133 g, 77%) as a white solid. To a solution of aminoglutarimide trifluoroacetate (163 mg) and triethylamine (1 mL) in THF (10 mL) was added anhydride 13 (133 mg). The mixture was refluxed for 16 h.
  • reaction of thalidomide 1 with Lawesson's reagent when stirred in benzene at 80° C. for 48 h, yielded thionamide 15 in a yield of 38%.
  • thionamide 15 in a yield of 38%.
  • a trace of dithionimide 16 (1.6%) was also obtained.
  • the yield proved to be very low (less than 2%) when the reaction of monothiothalidomide with Lawesson's reagent was performed between 80° C. to 120° C. The situation changed greatly when organic base was added to the reaction mixture.
  • 1,3-Dioxo-2-(2-oxo-6-thioxopiperidin-3-yl)isoindoline (15) was synthesized and isolated as follows. A mixture of thalidomide (170 mg, 0.658 mmol) and Lawesson's reagent (293 mg, 0.724 mmol) in benzene (50 ml) was stirred in a 80° C. oil bath for 2 days. The solvent was removed under vacuum.
  • 3-(2,6-Dioxopiperidin-3-yl)benzoxazine-2,4-dione (20) was prepared and isolated as follows. To a cold ice/salt solution of salicylic acid (100 mg) and triethylamine (303 ml) in chloroform (10 mL) was added ethyl chloroformate (157 ml). The reaction mixture was allowed to warm to room temperature, and, thereafter, stirring was continued for 3 h. The solvent was removed under vacuum to give crude 19. Without further purification, crude compound 19 was dissolved in CHCl 3 and cooled with ice. To the ice cold solution was added amine (95 mg). The reaction mixture was allowed to warm to ambient temperature and stirred at room temperature overnight.
  • 1-(2,6-Dioxo-3-piperidinylidene)-3-oxoisoindoline (23) was specifically prepared and isolated as follows. A mixture of 21 (16 mg, 0.1 mmol), 22 (19 mg, 0.1 mmol), and potassium carbonate (100 mg) in anhydrous THF was refluxed for 7 h. Thin-layer chromatography (TLC) showed that the starting materials had disappeared. Ethyl acetate (20 ml) and water (10 ml) were added. The organic layer was separated, dried over Na 2 SO 4 and concentrated under vacuum.
  • 2-acetoxy-N-(2,6-dioxopiperidin-3-yl)benzamide (24) was prepared as follows. To an ice cold solution of acetylsalicyloylchloride (252 mg) and triethylamine (0.58 mL) in chloroform (30 mL) was added 3-aminoglutaride trifluoroacetate (207 mg). The reaction temperature was allowed to warm to room temperature and stirring was continued overnight.
  • Monothiothalidomide 205 (same as compound 15 in Example 7) was prepared as shown in Scheme 11.
  • tert-Butoxycarbonyl-L-glutamine 202 was refluxed with carbonyl diimidazole (CDI) in THF, and cyclized to afford imide 203 (Muller et al., “Amino-substituted thalidomide analogs: potent inhibitors of TNF- ⁇ production,” Bioorg Med. Chem, Lett. 9, 1625-1630, 1999).
  • Imide 203 then was treated with trifluoroacetic acid in CH 2 Cl 2 to remove the protective group to generate aminoglutarimide trifluoroacetate 204. Without further purification, compound 204 was reacted with phthalic anhydride in refluxing THF in the presence of triethylamine to produce thalidomide 201 (same as compound 1 in Example 7) in the total yield of 31% from compound 202.
  • Thalidomide 201 was thionated with Lawesson's reagent (LR, Cava et al., “Thionation reaction of Lawesson's Reagents,” Tetrahedron, 41, 5061-5087, 1985, the entirety of which is incorporated herein by reference) to generate a single new product that had a structure identified as 6′-thiothalidomide 205 by mass spectrometry and 1D & 2D nuclear magnetic resonance spectroscopy.
  • the position of the thiocarbonyl group was established from the heteronuclear multiple bond correlation (HMBC) cross peak of H-5′/C-6′.
  • HMBC heteronuclear multiple bond correlation
  • 3-thiothalidomide, 212 could not be prepared through the cyclization of compound 208 with ammonia or amine as ammonia reacts with the thioamide; reaction of compound 208 with benzylamine produced the unexpected compound 210.
  • compound 208 was hydrolyzed under acidic conditions to give diacid 211.
  • Compound 211 was then reacted with trifluoroacetamide to generate 3-thiothalidomide 212 in the presence of 1-hydroxybenzotriazole (HOBt) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, Flaih et al., “An expeditious synthesis of cyclic imides,” Tetrahedron Lett. 40, 3697-3698, 1999).
  • HOBt 1-hydroxybenzotriazole
  • EDCI 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
  • monothiothalidomide 205 was thionated with LR to produce two dithiothalidomides, 213 (same as compound 16 in Example 7) and 215 (same as compound 17 in Example 7), in yields of 45% and 31%, respectively (Scheme 13 b,c).
  • Dithiothalidomide 213 was further thionated with LR in the presence of the stronger base, morpholine, to give trithiothalidomide 216 (same as compound 18 in Example 7) in a yield of 65%.
  • Glutarimide 217 was thionated with LR in THF at room temperature to afford compound 218 as a major product. Glutarimide 217 also was refluxed with LR in toluene to produce dithioglutarimide 219 (Scheme 15). Reaction of potassium phthalimide with 3-bromocyclohexene in a Gabriel reaction gave compound 221. Thereafter, thionation of compound 221 with LR afforded compounds 222 and 223 (Scheme 16). Compounds 224 and 225 were prepared in a similar procedure to that used in the preparation of compounds 222 and 223.
  • PBMC peripheral blood mononuclear cells
  • the Ficoll/serum interface containing PBMCs, was collected, diluted to 200 ml with PBS, and then was centrifuged (800 g, 15 min) to pellet the cells. Thereafter, the recovered pellet was re-suspended in 37° C. tissue culture medium (RPMI/1 mM Sodium pyruvate/10% heat inactivated FBS/2 mM Glutamax) and placed on ice. Recovered cells were counted, pipetted (200 ul of 5 ⁇ 10 5 /ml) into 96 well plates, and incubated for an hour (37° C., 5% CO 2 ). Thereafter, appropriate concentrations of test compounds or vehicle (10 ul DMSO) were added to duplicate wells.
  • RPMI/1 mM Sodium pyruvate/10% heat inactivated FBS/2 mM Glutamax 37° C. tissue culture medium
  • Recovered cells were counted, pipetted (200 ul of 5 ⁇ 10 5 /ml) into 96 well plates,
  • LPS lipopolysaccharide
  • M303E specific capture and detection monoclonal antibodies
  • test drug concentrations on the cellular viability of PBMCs was assessed by MTS assay (Promega, Madison, Wis.) of the cells that provided the supernatant samples assayed for TNF- ⁇ levels, described above. It should be understood that this method can be used to test any of the disclosed compounds as a screening assay for readily determining their TNF- ⁇ modulating activity, and for selecting them for use in the disclosed method of treating a subject.
  • Thalidomide, 201 entirely lacked activity at 30 ⁇ M. A concentration of 100 ⁇ M was required for significant activity (IC 50 ⁇ 200 ⁇ M).
  • the monothiothalidomides, 6′-thiothalidomide 205 and 3-thiothalidomide 212 showed only marginal activity at 30 ⁇ M with 31% and 23% inhibition of TNF- ⁇ secretion, respectively.
  • Trithiothalidomide 216 inhibited TNF- ⁇ production with an IC 50 of 6 ⁇ M, without accompanying toxicity. Compared with thalidomide, 201, with an IC 50 of ⁇ 200 ⁇ M for the inhibition of TNF- ⁇ synthesis, trithiothalidomide 216 is over 30-fold more active. Hence, successive replacement of a carbonyl with a thiocarbonyl group led to improved inhibitory activity compared to 201, unassociated with toxicity.
  • the synthesized thiothalidomides possessed TNF- ⁇ lowering potency in the following decreasing order: trithiothalidomide 216>dithiothalidomide 215 and 213>monothiothalidomides 205 and 212>thalidomide, 201.
  • the dithio analog, 209 proved 2-fold more potent still than 208, but induced cellular toxicity at lower concentrations.
  • thio analogs 222 and 223, with a simplified glutarimide ring were found to be active TNF- ⁇ inhibitors, albeit with some toxicity at 30 ⁇ M, with IC 50 values (15 ⁇ M and 16 ⁇ M respectively) that were greater than 212 (>30 ⁇ M possessing a normal glutarimide ring.
  • thalidomide is composed of two distinct moieties: the glutarimide and phthalimide rings.
  • Thioglutarimides and thiophthalimides were thus synthesized and evaluated to assess the effect of thio-analogs of these two moieties on TNF- ⁇ levels.
  • Monothioglutarimide 218 minimally inhibited TNF- ⁇ secretion at a concentration of 30 ⁇ M, however dithioglutarimide 219 exerted a potent inhibitory effect with an IC 50 of 8 ⁇ M and a lack of toxicity.
  • dithioglutarimide 219 proved to be 25-fold more active than thalidomide 201.
  • 2′,6′-dithiothalidomide 213, a phthalimido substituted dithioglutarimide is less active than dithioglutarimide 219, and induces toxicity at high concentration.
  • Monothiophthalimide 225 showed marginal TNF- ⁇ activity at a concentration of 30 ⁇ M without toxicity.
  • dithiophthalimide 224 was found to possess potent activity with an IC 50 of 3 ⁇ M. Although it was associated with toxicity at 30 ⁇ M, its inhibition of TNF- ⁇ occurred at an order of magnitude lower concentration that was well tolerated.
  • AREs adenylate/uridylate
  • UTR 3′-untranslated region
  • AREs adenylate/uridylate
  • the stability of TNF- ⁇ mRNA is largely regulated at its 3′-UTR, which contains a well characterized ARE.
  • AREs are found in a number of different cytokine and protooncogene RNAs, the pathways by which they induce degradation are highly specific for a given ARE indicating some cellular specificity.
  • FIG. 1 This cell-based assay utilized two stably transfected cell lines derived from the mouse macrophage line, RAW264.7. One line, designated “luciferase only” expressed a luciferase reporter construct without any UTR sequences. The other line, designated “luciferase+TNF- ⁇ UTR” expressed a luciferase reporter construct with the entire 3′-UTR of human TNF- ⁇ inserted directly downstream of the luciferase coding region.
  • compounds 215, 216 and 219 in cells possessing a luciferase reporter element plus the 3′-UTR of human TNF - ⁇ compared to cells lacking the 3′-UTR are shown in FIG. 1 .
  • Compounds 215, 216 and 219 exerted differential effect on the two cell lines in a dose-dependent manner, consistent with their ability to inhibit TNF- ⁇ production via the 3′-UTR. All agents lowered luciferase reporter activity in cells stably expressing the 3′-UTR. Thalidomide lacked activity at 50 ⁇ M.
  • cytokines including TNF- ⁇ , and iron can up regulate APP protein synthesis at the level of its 5′-UTR, where, interestingly, the anticholinesterase, phenserine, that is currently in clinical trials for AD, lowers APP protein levels with concurrent maintenance of mRNA steady-state levels through translational modification within the same 5′-UTR element.
  • HAV-1 human immunodeficiency virus 1
  • tat Trans-activating transduction
  • TAR trans-activation-responsive region
  • thalidomide (201) has been reported to lower cyclooxygenase-2 (Cox-2) biosynthesis via its 3′-UTR that appears to likewise contain an ARE that can regulate Cox-2 mRNA stability.
  • the studies of analogs 215, 216 and 219 confirm regulation of TNF- ⁇ protein levels by thalidomide (201) via its 3′-UTR, but whether or not the 5′-UTR contains a similar element that is accessible to pharmacological manipulation remains to be determined, as does action against Cox-2.
  • thiothalidomide analogs include analogs that are more potent inhibitors of TNF- ⁇ production in LPS-induced human PBMCs than thalidomide 201.
  • the isosteric replacement of successive carbonyl groups by a thiocarbonyl leads to an increasing inhibition with the number of moieties replaced (trithiothalidomide 216>dithiothalidomide 215 and 213>monothiothalidomides 205 and 212>thalidomide 201).
  • TNF- ⁇ has been validated as a drug target for two drugs on the market; Remicade (Cetocor, Malvern, Pa.; Schering-Plough, Orange, N.J.) and Enbrel (Amgen, Thousand Oaks, Calif.; Wyeth-Ayerst, Princeton, N.J.).
  • Remicade Chemocor, Malvern, Pa.; Schering-Plough, Orange, N.J.
  • Enbrel Amgen, Thousand Oaks, Calif.; Wyeth-Ayerst, Princeton, N.J.
  • both of these drugs are large macromolecules and hence require injection.
  • the small molecule drugs disclosed herein offer a means to potently and safely inhibit TNF- ⁇ without injection, for example, by oral administration.
  • 6-Thioxo-2-piperidinone (218).
  • Dithiophthalimide (225). A mixture of phthalimide (436 mg, 3.40 mmol) and Lawesson's reagent (1.199 g, 3.40 mmol) in toluene (50 ml) was refluxed (oil bath 120° C.) under nitrogen for 5 hours. The solvent was removed under vacuum and the residue was directly chromatographed (silica gel, petroleum ether:methylenedichloride/2:3) to give dithiophthalimide as black red needle crystals (240 mg, 39.4%): 1 HNMR(CDCl 3 ) ⁇ 9.80 (br, 1H), 7.95 (d, 2H), 7.80 (d, 2H); MS (CI/CH 4 ) m/z 179 (M + ).
  • 4-(t-Butoxycarbonyl amido)salicylic acid (226) was prepared as follows. To a mixture of 4-aminosalicylic acid (306 mg, 2 mmol) and di-t-butyl dicarbonate (655 mg, 3 mmol) in H 2 O was added NaOH (2N in H 2 O) at 0° C. This reaction mixture was allowed to warm to room temperature and then was stirred for 5 hours. 2N HCl was added dropwise until the mixture was neutralized.
  • Angiogenesis is the formation of new blood vessels from pre-existing vessels. Angiogenesis is prominent in solid tumor formation and metastasis, and is part of the wound healing process. Pathological angiogenesis sometimes occurs in inappropriate anatomic locations, such as the retina or cornea, in response to disease and injury. Inhibition of angiogenesis could avoid the progression of conditions of inappropriate angiogenesis.
  • Tumor formation requires a network of blood vessels to sustain the nutrient and oxygen supply for continued growth.
  • Tumors in which angiogenesis is important include most solid tumors and benign tumors, such as acoustic neuroma, neurofibroma, trachoma, and pyogenic granulomas. Inhibition of angiogenesis could halt the growth of these tumors and the resultant damage due to the presence of the tumor.
  • tumor microvessel density There is a direct correlation between tumor microvessel density and the incidence of metastasis.
  • Tumor cells themselves can produce factors that stimulate the proliferation of endothelial cells and new capillary growth.
  • Angiogenesis is important in two stages of tumor metastasis. The first stage where angiogenesis stimulation is important is in the vascularization of the primary tumor, which allows tumor cells to enter the blood stream and to circulate throughout the body. After the tumor cells have left the primary site, and have settled into the secondary, metastatic site, angiogenesis must occur before the metastasis can grow and expand. Therefore, inhibiting angiogenesis could lead to the reduction or elimination of metastasis of tumors and possibly contain the neoplastic growth at the primary site.
  • the angiogenesis modulating activity of representative compounds was assessed in a rat aortic ring microvessel growth assay. Briefly, twelve-well tissue culture plates were coated with 250 ⁇ l of Matrigel (Becton-Dickinson, Bedford, Mass.) and allowed to gel for 30 min at 37° C. and 5% CO 2 . Thoracic aortas were excised from 8- to 10-week-old male Sprague Dawley rats. After careful removal of fibroadipose tissues, the aortas were cut into 1-mm-long cross-sections, placed on Matrigel-coated wells, and covered with an additional 250 ⁇ l of Matrigel.
  • Matrigel Becton-Dickinson, Bedford, Mass.
  • EGM-II consists of endothelial cell basal medium (EBM-II; Clonetics, San Diego, Calif.) plus endothelial cell growth factors provided as the EGM-II Bulletkit (Clonetics).
  • EBM-II endothelial cell basal medium
  • EGM-II Bulletkit Clonetics
  • the culture medium was subsequently changed to EBM-II supplemented with 2% fetal bovine serum, 0.25 ⁇ g/ml amphotericin B, and 10 ⁇ g/ml gentamicin.
  • Aortic rings were treated daily with either the vehicle (0.5% DMSO), carboxyamidotriazole (CA, 12 ⁇ g/ml), thalidomide or thalidomide analogs (0.1-20 ⁇ g/ml) for 4 days and photographed on the 5th day using a ⁇ 2.5 objective.
  • CAI carboxyamidotriazole
  • thalidomide or thalidomide analogs 0.1-20 ⁇ g/ml
  • FIGS. 2-11 Bar graphs showing the results of the angiogenesis assay for several compounds are shown in FIGS. 2-11 . For convenience, the structures of the assayed compounds also are presented in these figures.
  • FIG. 2 shows the angiogenic modulating activity of 1,3-Dioxo-2-(2-hydroxy-6-methoxypyridin-3-yl)-isoindoline hydrobromide at several concentrations. This compound exhibited anti-angiogenic activity in the rat aortic ring assay at all concentrations tested.
  • FIG. 3 shows the angiogenic modulating activity of 2-(3-cyclohexenyl)-H-isoindol -1,3(2H)-dithione at several concentrations. This compounds exhibited anti-angiogenic activity at higher concentrations and angiogenic activity at lower concentrations.
  • FIG. 4 shows the angiogenic modulating activity of 1-(2,6-Dithioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione at several concentrations. This compound exhibited anti-angiogenic activity at all concentrations tested.
  • FIG. 5 shows the angiogenic modulating activity of 3-Camphanic amino-2,6-piperidinedione at several concentrations. This compound exhibited potent angiogenic activity at all concentrations tested, making this compound promising for treating conditions where increased angiogenesis is desired, for example, as an aid to wound healing.
  • FIG. 6 shows the angiogenic modulating activity of Dithiophthalimide at several concentrations. This compound exhibited angiogenic activity at all concentrations tested.
  • FIG. 7 shows the angiogenic modulating activity of 2-(1,3-Dihydro-1-oxo-3-thioxo-2H-isoindol-2-yl)-pentanedioic acid at several concentrations. This compound exhibited angiogenic activity at all concentrations tested.
  • FIG. 8 shows the angiogenic modulating activity of 2-(2-Oxo-6-thioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione at several concentrations. This compound showed anti-angiogenic activity at higher concentration, and some angiogenic activity at lower concentrations.
  • FIG. 9 shows the angiogenic modulating activity of 2,3-Dihydro-3-thioxo-2-(2,6-dithioxo-3-piperidinyl)-1H-isoindol-1-one at several concentrations. This compound exhibited potent anti-antigiogenic activity at higher concentrations and angiogenic activity at lower concentrations.
  • FIG. 10 shows the angiogenic modulating activity of 2-Acetoxy-N-(2,6-dioxopiperidin-3-yl)benzamide at several concentrations. At all concentrations tested, this compound exhibited potent angiogenic activity.
  • FIG. 11 shows the angiogenic modulating activity of 1,3-Dioxo-2-(2,6-dimethoxypyridin-3-yl)-isoindoline at several concentrations. This compound exhibited angiogenic activity at all concentrations tested.
  • the disclosed compounds exhibit a range of angiogenic modulating activities ranging from potent inhibition of angiogenesis (anti-angiogenic activity) to potent stimulation of angiogenesis (angiogenic activity).
  • Some compounds exhibit both angiogenic and anti-angiogenic activity in a dose-dependent manner.
  • Those compounds (or particular concentrations thereof) having angiogenic activity are useful for treating conditions or diseases where increasing angiogenesis is desirable (for example, wound healing) and those compounds (or particular concentrations thereof) having anti-angiogenic activity are useful for treating conditions or diseases where decreasing angiongenesis is desirable (for example, cancers, diabetic retinopathy or corneal neovascularization).
  • thionyl groups any of the carbonyl groups shown in the structures of the disclosed compounds may be converted into thiocarbonyl groups, and that such thio-derivatives are part of this disclosure.
  • Thionation may be accomplished by any known method. Particular methods of thionation include use of phosphorus pentasulfide, hydrogen sulfide, O,O-diethyldithiophosphonic acid, boron sulfide, silicon disulfide and elemental sulfur in HMPA.
  • thionation is the use of 2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide and its derivatives (generically “Lawesson's Reagents”). These reagents are described in Cava and Levinson, “Thionation Reactions of Lawesson's Reagents,” Tetrahedron, 41: 5061-5087, 1985, which is incorporated by reference herein.
  • compositions can be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions (e.g., eye or ear drops, throat or nasal sprays, etc.), transdermal patches, and other forms known in the art.
  • parenteral solutions or suspensions e.g., eye or ear drops, throat or nasal sprays, etc.
  • transdermal patches and other forms known in the art.
  • compositions can be administered systemically or locally in any manner appropriate to the treatment of a given condition, including orally, parenterally, rectally, nasally, buccally, vaginally, topically, optically, by inhalation spray, or via an implanted reservoir.
  • parenterally as used herein includes, but is not limited to subcutaneous, intravenous, intramuscular, intrasternal, intrasynovial, intrathecal, intrahepatic, intralesional, and intracranial administration, for example, by injection or infusion.
  • the pharmaceutical compositions may readily penetrate the blood-brain barrier when peripherally or intraventricularly administered.
  • Pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffers such as phosphates
  • glycine glycine
  • sorbic acid
  • Tablets and capsules for oral administration can be in a form suitable for unit dose presentation and can contain conventional pharmaceutically acceptable excipients.
  • binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth, and polyvinylpyrrolidone
  • fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine
  • tableting lubricants such as magnesium stearate, talc, polyethylene glycol, or silica
  • disintegrants such as potato starch
  • dispersing or wetting agents such as sodium lauryl sulfate.
  • Oral liquid preparations can be in the form of; for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • compositions can also be administered parenterally in a sterile aqueous or oleaginous medium.
  • the composition can be dissolved or suspended in a non-toxic parenterally-acceptable diluent or solvent, e.g., as a solution in 1,3-butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent e.g., as a solution in 1,3-butanediol.
  • Commonly used vehicles and solvents include water, physiological saline, Hank's solution, Ringer's solution, and sterile, fixed oils, including synthetic mono- or di-glycerides, etc.
  • the drug may be made up into a solution, suspension, cream, lotion, or ointment in a suitable aqueous or non-aqueous vehicle.
  • Additives may also be included, for example, buffers such as sodium metabisulphite or disodium edeate; preservatives such as bactericidal and fungicidal agents, including phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents, such as hypromellose.
  • buffers such as sodium metabisulphite or disodium edeate
  • preservatives such as bactericidal and fungicidal agents, including phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents, such as hypromellose.
  • the dosage unit involved depends, for example, on the condition treated, nature of the formulation, nature of the condition, embodiment of the claimed pharmaceutical compositions, mode of administration, and condition and weight of the patient. Dosage levels are typically sufficient to achieve a tissue concentration at the site of action that is at least the same as a concentration that has been shown to be active in vitro, in vivo, or in tissue culture.
  • a dosage of about 0.1 ⁇ g/kg body weight/day to about 1000 mg/kg body weight/day for example, a dosage of about 1 ⁇ g/kg body weight/day to about 1000 ⁇ g/kg body weight/day, such as a dosage of about 5 ⁇ g/kg body weight/day to about 500 ⁇ g/kg body weight/day can be useful for treatment of a particular condition.
  • the compounds can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids and bases, including, but not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate
  • Base salts include, but are not limited to, ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts with organic bases (such as dicyclohexylamine salts), N-methyl-D -glucamine, and salts with amino acids (such as arginine, lysine, etc.).
  • Basic nitrogen-containing groups can be quaternized, for example, with such agents as C1-8 alkyl halides (such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (such as dimethyl, diethyl, dibutyl, an diamyl sulfates), long-chain halides (such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (such as benzyl and phenethyl bromides), etc. Water or oil-soluble or dispersible products are produced thereby.
  • C1-8 alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, an dia
  • compositions can be included in a kit accompanied by instructions for intended use, for example instructions required by a pharmaceutical regulatory agency, such as the Food and Drug Administration in the United States.

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US20080176900A1 (en) * 2005-09-27 2008-07-24 Hesheng Zhang 5H-THIOENO(3,4-c)PYRROLE-4,6-DIONE DERIVATIVES AND THEIR USE AS TUMOR NECROSIS FACTOR INHIBITORS
US20090298882A1 (en) * 2008-05-13 2009-12-03 Muller George W Thioxoisoindoline compounds and compositions comprising and methods of using the same
US20100292243A1 (en) * 2009-05-12 2010-11-18 Albany Molecular Research, Inc. 7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF
US20130143922A1 (en) * 2011-12-02 2013-06-06 Nigel H. Greig Thio compounds
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US20160024048A1 (en) * 2007-03-20 2016-01-28 Celgene Corporation 4'-o-substituted isoindoline derivatives and compositions comprising and methods of using the same
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
WO2019079569A1 (en) 2017-10-18 2019-04-25 Novartis Ag COMPOSITIONS AND METHODS FOR SELECTIVE DEGRADATION OF A PROTEIN
US10730835B2 (en) 2015-09-30 2020-08-04 The United States Of America, As Represented By The Secretary, Health And Human Services Thalidomide analogs and methods of use
WO2020219742A1 (en) 2019-04-24 2020-10-29 Novartis Ag Compositions and methods for selective protein degradation
US11324731B2 (en) 2018-09-13 2022-05-10 City Of Hope TXNIP-TRX complex inhibitors and methods of using the same
WO2024097932A1 (en) * 2022-11-04 2024-05-10 Bristol-Myers Squibb Company Compounds and their use for treatment of hemoglobinopathies

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2929331B2 (ja) * 1990-07-18 1999-08-03 丸善石油化学株式会社 トラクションドライブ用流体
CN100383139C (zh) * 2005-04-07 2008-04-23 天津和美生物技术有限公司 可抑制细胞释放肿瘤坏死因子的哌啶-2，6-二酮衍生物
US20080064876A1 (en) * 2006-05-16 2008-03-13 Muller George W Process for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
US8877780B2 (en) 2006-08-30 2014-11-04 Celgene Corporation 5-substituted isoindoline compounds
CA2660806C (en) * 2006-08-30 2015-06-16 Celgene Corporation 5-substituted isoindoline compounds
AU2013260742B2 (en) * 2007-03-20 2016-06-16 Celgene Corporation 4'-o-substituted isoindoline derivatives and compositions comprising and methods of using the same
US7723301B2 (en) * 2007-08-29 2010-05-25 The Board Of Trustees Of The University Of Arkansas Pharmaceutical compositions comprising an anti-teratogenic compound and applications of the same
SI3202461T1 (sl) 2010-02-11 2019-05-31 Celgene Corporation Derivati arilmetoksi izoindolina in sestavki, ki jih vsebujejo in metode uporabe le teh
EP2582836B1 (en) 2010-06-18 2018-03-07 Taiho Pharmaceutical Co., Ltd. Prpk-tprkb modulators and uses thereof
JP2015500001A (ja) 2011-12-14 2015-01-05 大鵬薬品工業株式会社 組換えｐｒｐｋ−ｔｐｒｋｂ及びその使用
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BR112021000395A2 (pt) 2018-07-11 2021-04-06 H. Lee Moffitt Cancer Center And Research Institute, Inc. Compostos imunomoduladores diméricos contra mecanismos baseados em cereblon
AU2019381688A1 (en) 2018-11-13 2021-06-03 Biotheryx, Inc. Substituted isoindolinones
WO2020124500A1 (zh) * 2018-12-20 2020-06-25 江苏凯迪恩医药科技有限公司 一种含氮杂环化合物、其制备方法及应用
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Citations (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2830991A (en) 1954-05-17 1958-04-15 Gruenenthal Chemie Products of the amino-piperidine-2-6-dione series
GB962857A (en) 1961-12-04 1964-07-08 Distillers Co Yeast Ltd Process for the production of imides
GB1049283A (en) 1962-04-14 1966-11-23 Distillers Co Yeast Ltd Substituted butyro-lactones and -thiolactones
US3314953A (en) 1964-03-16 1967-04-18 Richardson Merrell Inc 1-substituted-3-phthalimido-2, 5-dioxopyrrolidines
US3320270A (en) 1963-10-08 1967-05-16 Tri Kem Corp Certain 2-acylimidothiazole compounds
GB1075420A (en) 1965-05-08 1967-07-12 Gruenenthal Chemie Cyclic imide compounds and a process for their production
US3560495A (en) 1965-05-08 1971-02-02 Ernst Frankus 1-heterocyclic amino methyl or 1-heterocyclic hydrazino methyl-3-phthalimido or (3',6'-dithia-3',4',5',6'-tetrahydrophthalimido)-pyrrolidinediones-2,5 or piperidinediones-2,6
US3794641A (en) 1970-11-10 1974-02-26 Nehezvegyipari Kutato Intezet Substituted phthalimido-1,3,5-triazines
US4092147A (en) 1975-11-12 1978-05-30 American Cyanamid Company Method for controlling the relative stem growth of plants
US4291048A (en) 1978-07-06 1981-09-22 Joseph Gold Method of treating tumors and cancerous cachexia with L-tryptophan
CA2104776A1 (en) 1991-04-17 1992-10-18 Kurt Eger Thalidomide derivatives, method of manufacture and use thereof in medicaments
WO1994020085A1 (en) 1993-03-01 1994-09-15 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
WO1995017154A2 (en) 1993-12-23 1995-06-29 Andrulis Pharmaceuticals Corporation Use of thalidomide for treating neurocognitive disorders
WO1996020705A1 (en) 1994-12-30 1996-07-11 Celgene Corporation IMMUNOTHERAPEUTIC IMIDES/AMIDES AND THEIR USE FOR REDUCING LEVELS OF TNF$g(a)
WO1996020926A1 (en) 1994-12-30 1996-07-11 Celgene Corporation Substituted imides as tnf inhibitors
US5593900A (en) 1989-07-07 1997-01-14 Tryggvason; Karl Immunological methods for the detection of the human type IV collagen α5 chain
US5605684A (en) 1994-03-14 1997-02-25 Piacquadio; Daniel J. Topical thalidomide compositions for surface of mucosal wounds, ulcerations, and lesions
WO1997012625A1 (en) 1995-10-03 1997-04-10 Cytran, Ltd. Pharmaceutical angiostatic dipeptide compositions and methods of use thereof
WO1997023457A1 (en) 1995-12-26 1997-07-03 Celgene Corporation Imides as pde iii, pde iv and tnf inhibitors
CA2251060A1 (en) 1996-04-09 1997-10-16 Grunenthal Gmbh Acylated n-hydroxy methyl thalidomide prodrugs with immunomodulator action
WO1997037988A1 (de) 1996-04-09 1997-10-16 Grünenthal GmbH Acylierte n-hydroxymethyl thalidomid-prodrugs mit immunomodulatorischer wirkung
WO1997045117A1 (en) 1996-05-29 1997-12-04 Prototek, Inc. Prodrugs of thalidomide and methods for using same as modulators of t-cell function
WO1998003502A1 (en) 1996-07-24 1998-01-29 Celgene Corporation Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels
WO1998019649A2 (en) 1996-11-05 1998-05-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
WO1998025895A1 (en) 1996-12-13 1998-06-18 Eli Lilly And Company Inhibitors of the enzymatic activity of psa
US5783605A (en) 1995-02-27 1998-07-21 Kuo; Sheng-Chu Helper inducers for differentiation therapy and chemoprevention of cancer
CA2228385A1 (en) 1997-02-01 1998-08-01 Grunenthal Gmbh Compounds analogous to thalidomide from the class comprising piperdine-2,6-diones
US5789434A (en) 1994-11-15 1998-08-04 Bayer Corporation Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors
US5840724A (en) 1993-06-01 1998-11-24 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or
WO1999013873A1 (fr) 1997-09-15 1999-03-25 Klavdia Stepanovna Evlanenkova Agent permettant de traiter des malades souffrant de tumeurs
CA2248838A1 (en) 1997-10-06 1999-04-06 Grunenthal Gmbh An intravenous form of thalidomide for the therapy of immunological diseases
WO1999058096A2 (en) 1998-05-11 1999-11-18 Entremed, Inc. Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis
WO1999059960A1 (en) 1998-05-15 1999-11-25 Astrazeneca Ab Benzamide derivatives for the treatment of diseases mediated by cytokines
US6080742A (en) 1998-09-24 2000-06-27 Gruenenthal Gmbh Substituted benzamides
US6096768A (en) 1992-01-28 2000-08-01 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
CA2302886A1 (en) 1999-03-31 2000-09-30 Tieno Germann A stable aqueous solution of em 12
US20010041716A1 (en) 1999-12-02 2001-11-15 Laing Timothy J. Compositions and methods for locally treating inflammatory diseases
WO2002064083A2 (en) 2000-11-30 2002-08-22 The Children's Medical Center Corporation Synthesis of 3-amino-thalidomide and its enantiomers
WO2002068414A2 (en) 2001-02-27 2002-09-06 The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
US6458810B1 (en) 2000-11-14 2002-10-01 George Muller Pharmaceutically active isoindoline derivatives
US20020161023A1 (en) 1993-03-01 2002-10-31 D'amato Robert Method of treating diseases using 3-amino thalidomide
US6500845B1 (en) 1994-06-24 2002-12-31 Gruenenthal Gmbh Lactam derivatives as immunomodulating agents
US20030013739A1 (en) 1998-12-23 2003-01-16 Pharmacia Corporation Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia
US6518298B2 (en) 1997-10-16 2003-02-11 Entremed, Inc. Methods and compositions for inhibition of angiogenesis with EM-138
WO2003014315A2 (en) 2001-08-06 2003-02-20 The Children's Medical Center Corporation Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs
US20030045552A1 (en) * 2000-12-27 2003-03-06 Robarge Michael J. Isoindole-imide compounds, compositions, and uses thereof
US6555554B2 (en) 1996-07-24 2003-04-29 Celgene Corporation Isoindolines, method of use, and pharmaceutical compositions
EP1336602A1 (en) 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
WO2003097052A2 (en) 2002-05-17 2003-11-27 Celgene Corporation Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases
WO2004085422A1 (fr) 2003-03-27 2004-10-07 Tian Jin Hemay Bio-Tech Co., Ltd. Derives de thalidomide hydrosoluble
WO2005016326A2 (en) 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors

Patent Citations (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2830991A (en) 1954-05-17 1958-04-15 Gruenenthal Chemie Products of the amino-piperidine-2-6-dione series
GB962857A (en) 1961-12-04 1964-07-08 Distillers Co Yeast Ltd Process for the production of imides
GB1049283A (en) 1962-04-14 1966-11-23 Distillers Co Yeast Ltd Substituted butyro-lactones and -thiolactones
US3320270A (en) 1963-10-08 1967-05-16 Tri Kem Corp Certain 2-acylimidothiazole compounds
US3314953A (en) 1964-03-16 1967-04-18 Richardson Merrell Inc 1-substituted-3-phthalimido-2, 5-dioxopyrrolidines
US3560495A (en) 1965-05-08 1971-02-02 Ernst Frankus 1-heterocyclic amino methyl or 1-heterocyclic hydrazino methyl-3-phthalimido or (3',6'-dithia-3',4',5',6'-tetrahydrophthalimido)-pyrrolidinediones-2,5 or piperidinediones-2,6
GB1075420A (en) 1965-05-08 1967-07-12 Gruenenthal Chemie Cyclic imide compounds and a process for their production
US3794641A (en) 1970-11-10 1974-02-26 Nehezvegyipari Kutato Intezet Substituted phthalimido-1,3,5-triazines
US4092147A (en) 1975-11-12 1978-05-30 American Cyanamid Company Method for controlling the relative stem growth of plants
US4291048A (en) 1978-07-06 1981-09-22 Joseph Gold Method of treating tumors and cancerous cachexia with L-tryptophan
US5593900A (en) 1989-07-07 1997-01-14 Tryggvason; Karl Immunological methods for the detection of the human type IV collagen α5 chain
CA2104776A1 (en) 1991-04-17 1992-10-18 Kurt Eger Thalidomide derivatives, method of manufacture and use thereof in medicaments
WO1992018496A1 (de) 1991-04-17 1992-10-29 Grünenthal GmbH Neue thalidomidderivate, ein verfahren zu deren herstellung sowie die verwendung derselben in arzneimitteln
US6096768A (en) 1992-01-28 2000-08-01 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
US5629327A (en) 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
US6235756B1 (en) 1993-03-01 2001-05-22 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis by thalidomide
US20050004087A1 (en) 1993-03-01 2005-01-06 The Children's Medical Center Corporation Methods and compositions for treating an ocular neovascular disease
US5593990A (en) * 1993-03-01 1997-01-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US6071948A (en) 1993-03-01 2000-06-06 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
WO1994020085A1 (en) 1993-03-01 1994-09-15 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US5712291A (en) 1993-03-01 1998-01-27 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US20020161023A1 (en) 1993-03-01 2002-10-31 D'amato Robert Method of treating diseases using 3-amino thalidomide
US6469045B1 (en) 1993-03-01 2002-10-22 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis with EM-138
US6420414B1 (en) 1993-03-01 2002-07-16 The Children's Medical Center Corporation Amino derivatives of EM-138 and methods of treating angiogenesis with same
US5840724A (en) 1993-06-01 1998-11-24 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or
WO1995017154A2 (en) 1993-12-23 1995-06-29 Andrulis Pharmaceuticals Corporation Use of thalidomide for treating neurocognitive disorders
US5434170A (en) 1993-12-23 1995-07-18 Andrulis Pharmaceuticals Corp. Method for treating neurocognitive disorders
US5605684A (en) 1994-03-14 1997-02-25 Piacquadio; Daniel J. Topical thalidomide compositions for surface of mucosal wounds, ulcerations, and lesions
US6500845B1 (en) 1994-06-24 2002-12-31 Gruenenthal Gmbh Lactam derivatives as immunomodulating agents
US5789434A (en) 1994-11-15 1998-08-04 Bayer Corporation Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors
WO1996020705A1 (en) 1994-12-30 1996-07-11 Celgene Corporation IMMUNOTHERAPEUTIC IMIDES/AMIDES AND THEIR USE FOR REDUCING LEVELS OF TNF$g(a)
WO1996020926A1 (en) 1994-12-30 1996-07-11 Celgene Corporation Substituted imides as tnf inhibitors
US5783605A (en) 1995-02-27 1998-07-21 Kuo; Sheng-Chu Helper inducers for differentiation therapy and chemoprevention of cancer
WO1997012625A1 (en) 1995-10-03 1997-04-10 Cytran, Ltd. Pharmaceutical angiostatic dipeptide compositions and methods of use thereof
WO1997023457A1 (en) 1995-12-26 1997-07-03 Celgene Corporation Imides as pde iii, pde iv and tnf inhibitors
CA2251060A1 (en) 1996-04-09 1997-10-16 Grunenthal Gmbh Acylated n-hydroxy methyl thalidomide prodrugs with immunomodulator action
WO1997037988A1 (de) 1996-04-09 1997-10-16 Grünenthal GmbH Acylierte n-hydroxymethyl thalidomid-prodrugs mit immunomodulatorischer wirkung
US6417197B1 (en) 1996-04-09 2002-07-09 Gruenenthal Gmbh Acylated n-hydroxy methyl thalidomide prodrugs with immunomodulator action
WO1997045117A1 (en) 1996-05-29 1997-12-04 Prototek, Inc. Prodrugs of thalidomide and methods for using same as modulators of t-cell function
US6555554B2 (en) 1996-07-24 2003-04-29 Celgene Corporation Isoindolines, method of use, and pharmaceutical compositions
WO1998003502A1 (en) 1996-07-24 1998-01-29 Celgene Corporation Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels
WO1998019649A2 (en) 1996-11-05 1998-05-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
WO1998025895A1 (en) 1996-12-13 1998-06-18 Eli Lilly And Company Inhibitors of the enzymatic activity of psa
US6110941A (en) 1997-02-01 2000-08-29 Gruenenthal Gmbh Compounds analogous to thalidomide from the class comprising piperidine-2,6-diones
CA2228385A1 (en) 1997-02-01 1998-08-01 Grunenthal Gmbh Compounds analogous to thalidomide from the class comprising piperdine-2,6-diones
WO1999013873A1 (fr) 1997-09-15 1999-03-25 Klavdia Stepanovna Evlanenkova Agent permettant de traiter des malades souffrant de tumeurs
US6124322A (en) 1997-10-06 2000-09-26 Gruenenthal Gmbh Intravenous form of thalidomide for treating immunological diseases
CA2248838A1 (en) 1997-10-06 1999-04-06 Grunenthal Gmbh An intravenous form of thalidomide for the therapy of immunological diseases
US20030181428A1 (en) 1997-10-16 2003-09-25 Green Shawn J. Methods and compositions for inhibition of angiogenesis
US6518298B2 (en) 1997-10-16 2003-02-11 Entremed, Inc. Methods and compositions for inhibition of angiogenesis with EM-138
WO1999058096A2 (en) 1998-05-11 1999-11-18 Entremed, Inc. Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis
WO1999059960A1 (en) 1998-05-15 1999-11-25 Astrazeneca Ab Benzamide derivatives for the treatment of diseases mediated by cytokines
US6080742A (en) 1998-09-24 2000-06-27 Gruenenthal Gmbh Substituted benzamides
US20030013739A1 (en) 1998-12-23 2003-01-16 Pharmacia Corporation Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia
US6306879B1 (en) 1999-03-31 2001-10-23 Gruenenthal Gmbh Stable aqueous solution of 3-(1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2-6-dione
CA2302886A1 (en) 1999-03-31 2000-09-30 Tieno Germann A stable aqueous solution of em 12
US20010041716A1 (en) 1999-12-02 2001-11-15 Laing Timothy J. Compositions and methods for locally treating inflammatory diseases
US6458810B1 (en) 2000-11-14 2002-10-01 George Muller Pharmaceutically active isoindoline derivatives
US6762195B2 (en) 2000-11-14 2004-07-13 Celgene Corporation Pharmaceutically active isoindoline derivatives
WO2002064083A2 (en) 2000-11-30 2002-08-22 The Children's Medical Center Corporation Synthesis of 3-amino-thalidomide and its enantiomers
US20030045552A1 (en) * 2000-12-27 2003-03-06 Robarge Michael J. Isoindole-imide compounds, compositions, and uses thereof
WO2002068414A2 (en) 2001-02-27 2002-09-06 The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
WO2003014315A2 (en) 2001-08-06 2003-02-20 The Children's Medical Center Corporation Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs
EP1336602A1 (en) 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
WO2003097052A2 (en) 2002-05-17 2003-11-27 Celgene Corporation Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases
WO2004085422A1 (fr) 2003-03-27 2004-10-07 Tian Jin Hemay Bio-Tech Co., Ltd. Derives de thalidomide hydrosoluble
WO2005016326A2 (en) 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors

Non-Patent Citations (133)

* Cited by examiner, † Cited by third party
Title
"The Merck Index," Merck & Co. 2001.
Bartlett et al., "Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patents with metastatic malignant melanoma and other advanced cancers," British Journal of Cancer 90:955-961, 2004.
Bauer et al., "Inhibition of Angiogenesis by Thalidomide Requires Metabolic Activation, Which is Species-dependent," Biochemical Pharmacology 55:1827-1834, 1998.
Bray et al., "Improved Procedures for the Preparation of (+)-(1R, 2S, 4R)-4-Amino-2-Hydroxy-1-Hydroxymethyl Cyclopentane," Tetrahedron Letters 36(25):4483-4486, 1995.
Cava et al., "Thionation Reactions of Lawesson's Reagents," Tethrahedron 41(22):5061-5087, 1985.
Ching et al., "Interaction of thalidomide, phthalimide analogues of thalidomide and pentoxifylline with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid: concomitant reduction of serum tumour necrosis factor-alpha and enhancement of anti-tumour activity," British Journal of Cancer 78(3):336-343, 1998.
Corral et al., "Differential Cytokine Modulation and T Cell Activation by Two Distinct Classes of Thalidomide Analogues that are Potent Inhibitors of TNF-alpha," The Journal of Immunology 163:380-386, 1999.
Corral et al., "Differential Cytokine Modulation and T Cell Activation by Two Distinct Classes of Thalidomide Analogues that are Potent Inhibitors of TNF-α," The Journal of Immunology 163:380-386, 1999.
Dalgleish et al., "Thalidomide Analogues CC-5013 and CC-4047 Induce T cell Activation and IL-12 Production in Patients with Both Solid Tumours and Relapsed and Refractory Multiple Myeloma," British Journal of Cancer 88(Suppl. 1)S25-S54 (Abstract P14), 2003.
D'Amato et al., "Thalidomide is an inhibitor of angiogenesis," Proc. Natl. Acad. Sci. USA 91:4082-4085, 1994.
Davies et al., "Thalidomide (Thal) and Immunomodulatory Derivatives (IMiDs) Augment Natural Killer (NK) Cell Cytotoxicity in Multiple Myeloma (MM)," American Society of Hematology, 42nd Annual Meeting, San Francisco, CA, Dec. 1-5, 2000 (Abstract No. 3617).
Davies et al., "Thalidomide (Thal) and Immunomodulatory Derivatives (IMiDs) Augment Natural Killer (NK) Cell Cytotoxicity in Multiple Myeloma (MM)," VIIIth International Myeloma Workshop, Banff, Canada, May 4-8, 2001 (Abstract No. P222).
Davies et al., "Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma," Blood 98(1):210-216, 2001.
De et al., "Possible Antineoplastic Agents: III Synthesis of 6-Alky1-2-U4′Methoxyphalimido and 6-Alkyl-3-U3′-4′-Dimethoxyphenyl Glutarimides," J. Indian Chem. Soc. 53:1122-1125, 1976.
De et al., "Possible Antineoplastic Agents: III Synthesis of 6-Alky1-2-U4'Methoxyphalimido and 6-Alkyl-3-U3'-4'-Dimethoxyphenyl Glutarimides," J. Indian Chem. Soc. 53:1122-1125, 1976.
De et al., "Possible Antineoplastic Agents: Part IV-Synthesis & Antineoplastic Potency of N-Substituted alpha-(4,5-Dimethoxyphthalimido)gludarimides & N-Substituted beta-(4-Bromophenyl)glutarimides," Indian J. of Chem. 16B:510-512, 1978.
De et al., "Possible Antineoplastic Agents: Part IV—Synthesis & Antineoplastic Potency of N-Substituted α-(4,5-Dimethoxyphthalimido)gludarimides & N-Substituted β-(4-Bromophenyl)glutarimides," Indian J. of Chem. 16B:510-512, 1978.
Deckers et al., "Effect of Angiogenic and Antiangiogenic Compounds on the Outgrowth of Capillary Structures from Fetal Mouse Bone Explants," Laboratory Investigation 81(1):5-15, 2001.
Dibbs et al., "Thalidomide and Thalidomide Analogs Suppress TNFalpha Secretion by Myocytes," Circulation 98(17(Suppl), Abstract No. 1284):I247, 1998.
Dibbs et al., "Thalidomide and Thalidomide Analogs Suppress TNFα Secretion by Myocytes," Circulation 98(17(Suppl), Abstract No. 1284):I247, 1998.
Dredge et al., "A costimulatory thalidomide analog enhances the partial anti-tumor immunity of an autologous vaccination in a model of colorectal cancer," American Association for Cancer Research, 93rd Annual Meeting, San Francisco, CA, Apr. 6-10, 2002 (Abstract No. 491).
Dredge et al., "Angiogenesis inhibitors in cancer therapy," Current Opinion in Investigational Drugs 4(6):667-674, 2003.
Dredge et al., "Immunological Effects of Thalidomide and Its Chemical and Functional Analogs," Critical Reviews in Immunology 22(5&6):425-437, 2002.
Dredge et al., "Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects," British Journal of Cancer 87:1166-1172, 2002.
Dredge et al., "Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination is Mediated by Increased Th1-Type Immunity," The Journal of Immunology 168:4914-4919, 2002.
Dredge et al., "Recent developments in antiangiogenic therapy," Expert Opin. Biol. Ther. 2(8):953-966, 2002.
Dredge et al., "Thalidomide analogs as emerging anti-cancer drugs," Anti-Cancer Drugs 14:331-335, 2003.
Eisen et al., "Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer," British Journal of Cancer 82(4):812-817, 2000.
Fine et al., "Phase II Trial of the Antiangiogenic Agent Thalidomide in Patients with Recurrent High-Grade Gliomas," Journal of Clinical Oncology 18(4):708-715, 2000.
Folkes et al., "Oxidative activation of indole-3-acetic acids to cytotoxic species-a potential new role for plant auxins in cancer therapy," Biochemical Pharmacology 61(2):129-136, 2001.
Greig et al., "New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases. p53 and TNF-alpha Inhibitors, and GLP-1 Receptor Agonists," Ann. N.Y. Acad. Sci. 1035:290-315, 2004.
Greig et al., "New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases. p53 and TNF-α Inhibitors, and GLP-1 Receptor Agonists," Ann. N.Y. Acad. Sci. 1035:290-315, 2004.
Greig et al., "Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases," Acta Neurobiol Exp 64:1-9, 2004.
Greig et al., "Thalidomide-based TNF-α inhibitors for neurodegenerative diseases," Acta Neurobiol Exp 64:1-9, 2004.
Gupta et al., "Adherence of multiple myeloma cells to bone morrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications," Leukemia 15:1950-1961, 2001.
Gütschow et al., "Aza Analogues of Thalidomide: Synthesis and Evaluation as Inhibitors of Tumor Necrosis Factor-alpha Production In Vitro," Bioorganic & Medicinal Chemistry 9:1059-1065, 2001.
Gütschow et al., "Aza Analogues of Thalidomide: Synthesis and Evaluation as Inhibitors of Tumor Necrosis Factor-α Production In Vitro," Bioorganic & Medicinal Chemistry 9:1059-1065, 2001.
Hashimoto et al., "Novel Biological Response Modifiers Derived from Thalidomide," Current Medicinal Chemistry 5:163-178, 1998.
Hashimoto et al., "Structural Development of Biological Response Modifiers Based on Thalidomide," Bioorganic & Medicinal Chemistry 10:461-479, 2002.
Haslett et al., "Thalidomide and a Thalidomide Analogue Drug Costimulate Virus-Specific CD8+ T Cells In Vitro," The Journal of Infectious Diseases 187:946-955, 2003.
Hayashi et al., "Mechanisms Whereby Immunomodulatory Analogs of Thalidomide Augment Autologous NK Cell Anti-Myeloma Immunity," American Society of Hematology, 44th Annual Meeting, Philadelphia, PA, Dec. 6-10, 2002 (Abstract No. 3219).
He et al., "Synthesis of Thalidomide Analogs and Their Biological Potential For Treatment of Graft Versus Host Disease (GVHD)," American Chemical Society (Abstract No. 216), 1993.
Hernandez-Ilizaliturri et al., "Addition of Immunomodulatory Drugs CC5013 or CC4047 to Rituximab Enhances Anti-Tumor Activity in a Severe Combined Immunodeficiency (SCID) Mouse Lymphoma Model," American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 235).
Hess et al., "Synthesis and immunological activity of water-soluble thalidomide prodrugs," Bioorganic and Medicinal Chem. 9(5):1279-1291, 2001.
Hideshima et al., "Thalidomide (Thal) and Its Analogs Overcome Drug Resistance of Human Multiple Myeloma (MM) Cells to Conventional Therapy," American Society of Hematology, 42nd Annual Meeting, San Francisco, CA, Dec. 1-5, 2000 (Abstract No. 1313).
Jönsson, "Chemical structure and teratogenic properties," Acta Pharm. Suecica 9:521:542, 1972.
Karbownik et al., "Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: relevance to cancer reduction," Journal of Cellular Biochemistry 81(3):507-513, 2001.
Kim et al., "Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo," Nature 362:841-844, 1993.
Kumar et al., "Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs," Leukemia 19:1253-1561, 2005.
Lentzsch et al., "Immunomodulatory Derivatives of Thalidomide (IMiD CC-4047) Determine the Lineage Commitment of Hematopoietic Progenitors by Down Regulation of GATA-1 and Modulation of Cytokine Secretion," American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 3073).
Lentzsch et al., "Immunomodulatory Derivatives of Thalidomide (IMiD CC-4047) Down Regulates CAAT/Enhancer-Binding Protein beta(C/EBPbeta) in Multiple Myeloma (MM)", American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 3456).
Lentzsch et al., "Immunomodulatory Derivatives of Thalidomide (IMiD CC-4047) Down Regulates CAAT/Enhancer-Binding Protein β(C/EBPβ) in Multiple Myeloma (MM)", American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 3456).
Lentzsch et al., "S-3-Amino-phthalimido-glutarimide Inhibits Angiogenesis and Growth of B-Cell Neoplasias in Mice," Cancer Research 62:2300-2305, 2002.
Lepper et al., "Comparative Molecular Field Analysis and Comparative Molecular Similarity Indices Analysis of Thalidomide Analogues as Angiogenesis Inhibitors," J. Med. Chem. 47:2219-2227, 2004.
Little et al., "Activity of Thalidomide in AIDS-Related Kaposi's Sarcoma," Journal of Clinical Oncology 18(13):2593-2602, 2000.
Luzzio et al., "Thalidomide metabolites and analogs. Part 2: Cyclic derivatives of 2-N-phthalimido-2S,3S (3-hydroxy) ornithine," Tetrahedron Letters 41:7151-7155, 2000.
Luzzio et al., "Thalidomide Metabolites and Analogues. 3. Synthesis and Antiangiogenic Activity of the Teratogenic and TNF-alpha-Modulatory Thalidomide Analogue 2-(2,6-Dioxopiperidine-3-yl)phthalimidine," Journal of Medicinal Chemistry 46(18):3793-3799, 2003.
Luzzio et al., "Thalidomide Metabolites and Analogues. 3. Synthesis and Antiangiogenic Activity of the Teratogenic and TNF-α-Modulatory Thalidomide Analogue 2-(2,6-Dioxopiperidine-3-yl)phthalimidine," Journal of Medicinal Chemistry 46(18):3793-3799, 2003.
Man et al., "alpha-Fluoro-Substituted Thalidomide Analogues," Bioorganic & Medicinal Chemistry Letters 13:3415-3417, 2003.
Man et al., "α-Fluoro-Substituted Thalidomide Analogues," Bioorganic & Medicinal Chemistry Letters 13:3415-3417, 2003.
Marriott et al., "A Novel Subclass of Thalidomide Analogue with Anti-Solid Tumor Activity in Which Caspase-dependent Apoptosis is Associated with Altered Expression of bcl-2 Family Proteins," Cancer Research 63:593-599, 2003.
Marriott et al., "CC-3052: A Water-Soluble Analog of Thalidomide and Potent Inhibitor of Activation-Induced TNF-alpha Production," The Journal of Immunology 161:4239-4243, 1998.
Marriott et al., "CC-3052: A Water-Soluble Analog of Thalidomide and Potent Inhibitor of Activation-Induced TNF-α Production," The Journal of Immunology 161:4239-4243, 1998.
Marriott et al., "Immunotherapeutic and antitumour potential of thalidomide analogues," Expert Opin. Biol. Ther. 1(4):1-8, 2001.
Marriott et al., "Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4+ and CD8+ T cells," Clin Exp Immunol 130:75-84, 2002.
Marriott et al., "Thalidomide and its analogues have distinct and opposing effects on TNF-α and TNFR2 during co-stimulation of both CD4+ and CD8+ T cells," Clin Exp Immunol 130:75-84, 2002.
Marriott et al., "Thalidomide Derived Immunomodulatory Drugs (IMiDs) as Potential Therapeutic Agents," Current Drug Targets-Immune, Endocrine & Metabolic Disorders 3:181-186, 2003.
Meierhofer et al., "New Insights into the pharmacological and toxicological effects of thalidomide," Current Opinion in Drug Discovery & Development 6(1):92-99, 2003.
Mitsiades et al., "Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications," Blood 99(12):4525-4530, 2002.
Miyachi et al., "Inducer-Specific Regulators of Tumor Necrosis Factor Alpha Production," Chem. Pharm. Bull 44(10):1980-1982, 1996.
Miyachi et al., "Novel Biological Response Modifiers: Phthalimides with Tumor Necrosis Factor-alpha Production-Regulating Activity," J. Med. Chem. 40(18):2858-2865, 1997.
Miyachi et al., "Novel Biological Response Modifiers: Phthalimides with Tumor Necrosis Factor-α Production-Regulating Activity," J. Med. Chem. 40(18):2858-2865, 1997.
Moutouh de Parseval et al., "Novel immunomodulatory drugs (IMiDs®): A potential, new therapy for beta-hemoglobinopathies," American Society of Hematology, 46th Annual Meeting, San Diego, CA, Dec. 4-7, 2004 (Abstract No. 3740).
Moutouh de Parseval et al., "Novel immunomodulatory drugs (IMiDs®): A potential, new therapy for β-hemoglobinopathies," American Society of Hematology, 46th Annual Meeting, San Diego, CA, Dec. 4-7, 2004 (Abstract No. 3740).
Muller et al., "Amino-Substituted Thalidomide Analogs: Potent Inhibitors of TNF-alpha Production," Bioorganic & Medicinal Chemistry Letters 9:1625-1630, 1999.
Muller et al., "Amino-Substituted Thalidomide Analogs: Potent Inhibitors of TNF-α Production," Bioorganic & Medicinal Chemistry Letters 9:1625-1630, 1999.
Neumann et al., "N-(Sulfonyloxy)phthalimides and Analogues Are Potent Inactivators of Serine Proteases," The Journal of Biological Chemistry 269(34):21561-21567, 1994.
Ng et al., "Antiangiogenic Activity of N-substituted and Tetrafluorinated Thalidomide Analogues," Cancer Research 63(12):3189-3194, 2003.
Ng et al., "Antitumor Effects of Thalidomide Analogs in Human Prostate Cancer Xenografts Implanted in Immunodeficient Mice," Clinical Cancer Research 10:4192-4197, 2004.
Ni et al., "Experimental study on activity of human recombinant adenovirus vector expressing human endostatin in vitro," Dier Junyi Daxue Xuebao Bianjibu 23(3):261-263, 2002 (Abstract only).
Niwayama et al., "Enhanced Potency of Perfluorinated Thalidomide Derivatives for Inhibition of LPS-Induced Tumor Necrosis Factor-alpha Production is Associated with a Change of Mechanism of Action," Bioorganic & Medicinal Chemistry Letters 8:1071-1076, 1998.
Niwayama et al., "Enhanced Potency of Perfluorinated Thalidomide Derivatives for Inhibition of LPS-Induced Tumor Necrosis Factor-α Production is Associated with a Change of Mechanism of Action," Bioorganic & Medicinal Chemistry Letters 8:1071-1076, 1998.
Niwayama et al., "Potent Inhibition of Tumor Necrosis Factor-alpha Production by Tetrafluorothalidomide and Tetrafluorophthalimides," J. Med. Chem. 39:3044-3045, 1996.
Niwayama et al., "Potent Inhibition of Tumor Necrosis Factor-α Production by Tetrafluorothalidomide and Tetrafluorophthalimides," J. Med. Chem. 39:3044-3045, 1996.
Orzeszko et al., "Tumor necrosis factor-alpha production-regulating activity of phthalimide derivatives in genetically modified murine melanoma cells B78H1," Il Farmaco 58:371-376, 2003.
Pagani et al., "Effetto Sul Geotropism Radicale di Semi di Lens Esculenta Moench s.l. di una Serie di Sostanze Correlate All'Acido N-alpha-Naftilftalamico," Farmaco Ed. Sci. 25:203-225, 1970.
Pagani et al., "Effetto Sul Geotropism Radicale di Semi di Lens Esculenta Moench s.l. di una Serie di Sostanze Correlate All'Acido N-α-Naftilftalamico," Farmaco Ed. Sci. 25:203-225, 1970.
Park et al., "Synthesis and Structure-Activity Relationships of Novel Compounds for the Inhibition of TNF-α Production," Arch Pharm Res 23(4): 332-337, 2000.
Patani et al., Bioisosterism: A Rational Approach in Drug Design, 1996, Chem. Rev., vol. 96, pp. 3147-3176. *
Patten et al., "The Early Use of the Serum Free Light Chain Assay in Patients with Relapsed Refractory Myeloma Receiving Treatment with a Thalidomide Analogue (CC-4047)," American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 1640).
Payvandi et al., "CC-5013 inhibits the expression of adhesion molecules ICAM-1 and CD44 and prevents metastasis of B16 F10 mouse melanoma cells in an animal model," American Society of Clinical Oncology, 39th Annual Meeting, Chicago, IL, May 31-Jun. 3, 2003 (Abstract No. 992).
Payvandi et al., "Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner," Cellular Immunology 230:81-88, 2004.
Payvandi et al., "Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-α, IL-1β, and LPS-stimulated human PBMC in a partially IL-10-dependent manner," Cellular Immunology 230:81-88, 2004.
Payvandi et al., "Thalidomide analogs IMiDs inhibit expression of cyclooxygenase-2 in multiple myeloma cell line and LPS stimulated PBMCs," American Society of Hematology, 43rd Annual Meeting, Orlando, FL, Dec. 7-11, 2001 (Abstract No. 2689).
Payvandi et al., "Thalidomide and IMiDs Inhibit Microvessel Formation from Human Arterial Rings in the Absence of Human Liver Microsomes," American Society of Hematology, 44th Annual Meeting, Philadelphia, PA, Dec. 6-10, 2002 (Abstract No. 5046).
Payvandi et al., "The thalidomide analogs IMiDs enhance expression of CD69 stimulatory receptor on natural killer cells," American Association of Cancer Research, 92nd Annual Meeting, New Orleans, LA, Mar. 24-28, 2001 (Abstract No. 1793).
Pratt et al., "Phthalic Acid Derivatives : Constitution and Color, XIV. Some Derivatives of Tetra-Bromophthalimide," J. Amer. Chem. Soc. 40:1415-1425, 1918.
Schafer et al., "Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs," The Journal of Pharmacology and Experimental Therapeutics 305(3):1222-1232, 2003.
Schey et al., "Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma," Journal of Clinical Oncology 22(16):1-8, 2004.
Sedlak et al., "Preparation, 1H and 13C NMR spectra of substituted 2-benzoylaminocarboxamides," Collection of Czechoslovak Chemical Communications, Academic Press 60:150-160, 1995.
Shah et al., "Synthesis and Enantiomeric Separation of 2-Phthalimidino-glutaric Acid Analogues: Potent Inhibitors of Tumor Metastasis," J. Med. Chem. 42(16):3014-3017, 1999.
Shaughnessy et al., "Global Gene Expression Analysis Shows Loss of C-MYC and IL-6 Receptor Gene mRNA After Exposure of Myeloma to Thalidomide and IMiD," The American Society of Hematology, 42nd Annual Meeting, San Francisco, CA, Dec. 1-5, 2000 (Abstract No. 2485).
Shimazawa et al., "Antiangiogenic Activity of Tumor Necrosis Factor-alpha Production Regulator Derived from Thalidomide," Biol. Pham. Bull. 22(2):224-226, 1999.
Shimazawa et al., "Antiangiogenic Activity of Tumor Necrosis Factor-α Production Regulator Derived from Thalidomide," Biol. Pham. Bull. 22(2):224-226, 1999.
Shimazawa et al., "Nonpeptide Small-Molecular Inhibitors of Dipeptidyl Peptidase IV: N-Phenylphthalimide Analogs," Bioorganic & Medicinal Chemistry Letters 9:559-562, 1999.
Shimazawa et al., "Novel Small Molecule Nonpeptide Aminopeptidase N Inhibitors with Cyclic Imide Skeleton," J. Enzyme Inhibition 14:259-275, 1999.
Shire et al., "TNF-alpha inhibitors and rheumatoid arthritis," Exp. Opin. Ther. Patents 8(5):531-544, 1998.
Shire et al., "TNF-α inhibitors and rheumatoid arthritis," Exp. Opin. Ther. Patents 8(5):531-544, 1998.
Singhal et al., "Antitumor Activity of Thalidomide in Refractory Multiple Myeloma," The New England Journal of Medicine 341(21):1565-1571, 1999.
Singhal et al., "Thalidomide in Cancer. Potential Uses and Limitations," BioDrugs 15(3):163-172, 2001.
Streetly et al., "An Update of the Use and Outcomes of the New Immunomodulatory Agent CC-4047 (Actimid) in Patients with Relapsed/Refractory Myeloma," American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 829).
Streetly et al., "Changes in Neutrophil Phenotype Following the Administration of CC-4047 (Actimid) to Patients with Multiple Myeloma," American Society of Hematology, 45th Annual Meeting, San Diego, CA, Dec. 6-9, 2003 (Abstract No. 2543).
Streetly et al., "Thalidomide analogue CC-4047 is effective in the treatment of patients with relapsed and refractory multiple myeloma (MM) and induces T-cell activation and IL-12 production," International Multiple Myeloma Workshop, IXth International Conference, Salamanca, Spain, May 23-27, 2003 (Abstract No. 367).
Suzuki, et al., "Use of a new protecting group in an attempted synthesis of cyclopropyldihydroxyphenylalanine," Journal of Organic Chemistry 48(24):4769-4771, 1983.
Teo et al., "Chiral Inversion of the Second Generation IMiD(TM) CC-4047 (ACTIMID(TM)) in Human Plasma and Phosphate-Buffered Saline," Chirality 15:348-351, 2003.
Teo et al., "Chiral Inversion of the Second Generation IMiD™ CC-4047 (ACTIMID™) in Human Plasma and Phosphate-Buffered Saline," Chirality 15:348-351, 2003.
Teubert et al., "5′-Substituted Thalidomide Analogs as Modulators of TNF-α," Arch. Pharm. Med. Chem. 331:7-12, 1998.
Teubert et al., "5′-Substituted Thalidomide Analogs as Modulators of TNF-α," Arch. Pharm. Pharm. Med. Chem. 331:7-12, 1998.
Teubert et al., "5'-Substituted Thalidomide Analogs as Modulators of TNF-alpha," Arch. Pharm. Med. Chem. 331:7-12, 1998.
Teubert et al., "5'-Substituted Thalidomide Analogs as Modulators of TNF-alpha," Arch. Pharm. Pharm. Med. Chem. 331:7-12, 1998.
Tsenova et al., "Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy for Experimental Tuberculous Meningitis," Antimicrobial Agents and Chemotherapy 46(6):1887-1895, 2002.
Tweedie et al., "TNF-alpha Synthesis Inhibitors on the 3-Phthalimidoglutarimide Backbone as Therapeutic Candidates for Neurodegenerative Diseases," 7th International Conference on Alzheimer's and Parkinson's Disease, pp. 77-86, Sorrento, Italy, Mar. 9-13, 2005.
Tweedie et al., "TNF-α Synthesis Inhibitors on the 3-Phthalimidoglutarimide Backbone as Therapeutic Candidates for Neurodegenerative Diseases," 7th International Conference on Alzheimer's and Parkinson's Disease, pp. 77-86, Sorrento, Italy, Mar. 9-13, 2005.
Voss, "2,4-Bis(4-methoxypheny1)-1,3,2,4-dithiadiphosphetane 2,4-Disulfide," e-EROS Encyclopedia of Reagents for Organic Synthesis, Sep. 15, 2006.
Voss, Juergen, 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane, 2001, Encyclopedia of Reagents for Organic Synthesis (e-EROS). Abstract only. *
Weinz et al., "Investigation of the in vitro biotransformation and simultaneous enantioselective separation of thalidomide and its neutral metabolites by capillary electrophoresis," Journal of Chromatography B 674:287-292, 1995.
Ye et al., "Novel IMiD Drugs Enhance Expansion and Regulate Differentiation of Human Cord Blood CD34+ Cells with Cytokines," American Society of Hematology, 44th Annual Meeting, Philadelphia, PA, Dec. 6-10, 2002 (Abstract No. 4099).
Zeldis et al., "Potential New Therapeutics for Waldenstrom's Macroglobulinemia," Seminars in Oncology 30(2):275-281, 2003.
Zeldis et al., "Update on the evolution of the IMiD™," International Society for Biological Therapy of Cancer, 18th Annual Meeting, Bethesda, MD, Oct. 30-Nov. 2, 2003 (Oral Abstract).
Zhang et al., "CC-5079, a novel microtubule and TNF-a inhibitor with anti-angiogenic and antimetastasis activity," American Association for Cancer Research, National Cancer Institute, and European Organization for Research and Treatment of Cancer, International Conference on Molecular Targets and Cancer Therapeutics, Boston, MA, Nov. 17-21, 2003 (Abstract No. B012).
Zhang et al., "Preparation of water-soluble thalidomide derivatives," Database CA Online Chemical Abstracts Service, Database Accession No. 2004:817880, 2004 (Abstract).
Zhu et al., "Thiothalidomides: Novel Isosteric Analogues of Thalidomide with Enhanced TNF-alpha Inhibitory Activity," J. Med. Chem. 26(24):5222-5229, 2003.
Zhu et al., "Thiothalidomides: Novel Isosteric Analogues of Thalidomide with Enhanced TNF-α Inhibitory Activity," J. Med. Chem. 26(24):5222-5229, 2003.

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US20130143922A1 (en) * 2011-12-02 2013-06-06 Nigel H. Greig Thio compounds
US10730835B2 (en) 2015-09-30 2020-08-04 The United States Of America, As Represented By The Secretary, Health And Human Services Thalidomide analogs and methods of use
US10836721B2 (en) 2015-09-30 2020-11-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thalidomide analogs and methods of use
US11440880B2 (en) 2015-09-30 2022-09-13 The Usa, As Represented By The Secretary, Department Of Health And Human Services Thalidomide analogs and methods of use
WO2019079569A1 (en) 2017-10-18 2019-04-25 Novartis Ag COMPOSITIONS AND METHODS FOR SELECTIVE DEGRADATION OF A PROTEIN
US11324731B2 (en) 2018-09-13 2022-05-10 City Of Hope TXNIP-TRX complex inhibitors and methods of using the same
US11974990B2 (en) 2018-09-13 2024-05-07 City Of Hope TXNIP-TRX complex inhibitors and methods of using the same
WO2020219742A1 (en) 2019-04-24 2020-10-29 Novartis Ag Compositions and methods for selective protein degradation
WO2024097932A1 (en) * 2022-11-04 2024-05-10 Bristol-Myers Squibb Company Compounds and their use for treatment of hemoglobinopathies

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CA2808646C (en) 2016-08-23
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US20060211728A1 (en) 2006-09-21
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